WO2011159635A1

WO2011159635A1 - Lysophosphatidic acid receptor antagonist for the treatment of dermal conditions

Info

Publication number: WO2011159635A1
Application number: PCT/US2011/040236
Authority: WO
Inventors: John Howard Hutchinson; Isabelle Marguerite Dearmond; Thomas Jon Seiders
Original assignee: Amira Pharmaceuticals Inc
Current assignee: Amira Pharmaceuticals Inc
Priority date: 2010-06-15
Filing date: 2011-06-13
Publication date: 2011-12-22
Anticipated expiration: 2012-12-15

Abstract

Described herein are LPA1 receptor antagonists, pharmaceutical compositions comprising at least one LPA1 receptor anatgonist, and methods of treating or preventing dermal diseases or conditions. Pharmaceutical compositions are suitable for systemic admistration or for topical administration.

Description

LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS FOR THE TREATMENT OF

DERMAL CONDITIONS

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S provisional patent application no. 61/355,103 entitled "LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS FOR THE TREATMENT OF DERMAL CONDITIONS" filed on June 15, 2010, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] Described herein are methods of treating or preventing dermal diseases or conditions in mammals with at least on LPAI receptor antagonist. Also described are pharmaceutical compositions that include at least one LPAI receptor antagonist in a form suitable for systemic or topical administration to a mammal.

BACKGROUND OF THE INVENTION

[0003] Lysophosphatidic acid (LPA) binding to its cognate G-protein coupled receptors (LPAi, LPA₂, LPA₃, LPA₄, LPA₅) activates intracellular signaling pathways and produces a variety of biological responses. Dermal diseases or conditions include, but are not limited to, iibrotic diseases or conditions, scarring, prolilferative diseases or conditions, and inflammatory diseases or conditions.

SUMMARY OF THE INVENTION

[0004] In one aspect, presented herein are compounds that inhibit the physiological activity of lysophosphatidic acid (LPA), and are useful as agents for the treatment or prevention of dermal diseases or conditions or diseases or conditions in which dermal tissues are affected. In some embodiments, such diseases or conditions will benefit from inhibition of the physiological activity of LPA, such as diseases in which an LPA receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. Such diseases or conditions include, but are not limited to skin fibrosis, cutaneous scleroderma, systemic sclerosis, Raynaud's phenomenon, keloids, recurrence of keloids post resection, scarring, hypertrophic scars, revision of scars, scars post-burns, Dupuytrens disease, cutaneous irradiation, capsular contracture, fibrosis post surgery.

[0005] In one aspect, LPAI receptor antagonists are useful for the treatment of dermal fibrosis, scarring, cell proliferative diseases involving dermal tissues, and inflammatory diseases or conditions involving dermal tissues. In one aspect, LPAI receptor antagonists are used in the treatment of iibrotic diseases or conditions involving dermal tissues.

[0006] In one aspect, the LPA compounds disclosed herein or contemplated herein (including pharmaceutically acceptable salts, solvates, and prodrugs thereof) are antagonists of at least one of the LPA receptors selected from LPAi, LPA₂, LPA₃, LPA_4; LPA₅ and LPA₆. In one embodiment, the LPA compounds are antagonists of LPA^ In one embodiment, the LPA compounds are antagonists of LPAi and/or LPA₃. In some embodiments, the LPA compounds are antagonists of LPAi and/or LPA₂. In some embodiments, the LPA compounds are selective antagonists for one of the LPA receptors relative to the other LPA receptors. In some embodiments, such a selective antagonist is selective for the LPAi receptor. In some embodiments, such a selective antagonist is selective for the LPA₂ receptor. In some embodiments, such a selective antagonist is selective for the LPA₃ receptor.

[0007] In some embodiments, described is a method of treating a dermal disease or condition in a mammal, comprising administering to the mammal in need thereof a therapeutically-effective amount of an LPAI receptor antagonist. In some embodiments, the dermal disease or condition is LPA-dependent or LPA-mediated. In some embodiments, the dermal disease or condition is LPA1- dependent or LPAI -mediated. In some embodiments, the dermal disease or condition is a fibrotic disease or condition. In some embodiments, the dermal disease or condition comprises undesired or abnormal fibrosis. In some embodiments, the dermal disease or condition is scleroderma, Raynaud's phenomenon; calcinosis, scarring, Dupuytren's disease; cutaneous irradiation syndrome; capsular contracture; retroperitoneal fibrosis; or a combination thereof. In some embodiments, the dermal disease or condition is cutaneous scleroderma or systemic scleroderma. In some embodiments, the dermal disease or condition is cutaneous scleroderma. In some embodiments, the dermal disease or condition is skin fibrosis, cutaneous scleroderma, systemic sclerosis, Raynaud's phenomenon, keloids, recurrence of keloids post resection, hypertrophic scars, revision of scars, scars post-burns, Dupuytrens disease, cutaneous irradiation syndrome, capsular contracture, and fibrosis post ligament and orthopedic surgery. In some embodiments, the dermal disease or condition is atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, keloid scar formation, scleroderma, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma or melanoma In some embodiments, the dermal disease or condition is scarring, a proliferative disease or condition, a fibrotic disease or condition or an inflammatory disease or condition.

[0008] In some embodiments, the dermal disease or condition is scarring. In some embodiments, the dermal disease or condition is hypertrophic scarring. In some embodiments, the scarring results in the formation of a keloid scar. In some embodiments, the scarring is a result of surgery performed on the mammal.

[0009] In some embodiments, the LPAI receptor antagonist is administered to the mammal prior to surgery. In some embodiments, the LPAI receptor antagonist is administered to the mammal after to surgery. In some embodiments, the LPAI receptor antagonist is administered to the mammal prior to and after surgery. [0010] In some embodiments, provided is a method of reducing undesired or abnormal dermal thickening in a mammal comprising administering to the mammal in need thereof a therapeutically- effective amount of an LPAl receptor antagonist.

[0011] In some embodiments, provided is a method of reducing undesired or abnormal dermal thickening associated with densely packed connective tissue in a mammal comprising administering to the mammal in need thereof a therapeutically-effective amount of an LPAl receptor antagonist.

[0012] In some embodiments, provided is a method of reducing undesired or abnormal dermal thickening associated with a fibrotic disease of condition in a mammal comprising administering to the mammal in need thereof a therapeutically-effective amount of an LPAl receptor antagonist.

[0013] In some embodiments, provided is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in dermal tissues of a mammal comprising administering a LPAl receptor antagonist to mammal. In some embodiments, the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the dermal tissues results in dermal fibrosis.

[0014] In some embodiments, provided is a method of reducing hydroxyproline content in dermal tissues of a mammal comprising administering a LPAl receptor antagonist to mammal. In some embodiments, the mammal has one of the dermal diseases or conditions described herein.

[0015] In some embodiments, provided is a method of reducing dermal vascular leakage in a mammal comprising administering a LPAl antagonist to mammal.

[0016] In some embodiments, the LPAl receptor antagonist has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), or a

pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (VI) or a pharmaceutically acceptable salt thereof. In some embodiments, the LPAl receptor antagonist has a structure of Formula (VII) or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the LPAl receptor antagonist is selected from LPAl receptor antagonists disclosed in: US Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional Application no. 61/121 ,862; US Provisional Application no. 61/231 ,282; US Provisional Application no. 61/247,681 ; US Provisional Application no. 61/2472877; International patent application no. PCT/US2010/44284; International patent application no. PCT US2010/51199; International patent application no. PCT US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786; International patent application no. PCT/US2010/50787; US Patent Application no. 12/893,902; International patent application no. PCT/US09/68106; International patent application no.

PCT/US09/68105; International patent application no. PCT/US09/67527; International patent application no. PCT/USlO/37309; International patent application no. PCT USlO/37316; or US Patent Application no. 12/793,440; each of which is herein incorporated by reference.

[0018] In some embodiments, the LPA1 receptor antagonist is (R)-2-(4'-(3-methyl-4-((l- phenyl ethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A); (R)-l-(4'-(3- methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)cyclopropanecarboxylic acid (Compound B); (R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5- yl)biphenyl-4-yl)acetic acid (Compound C); {5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)- biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound D); 1- (4'- {4-[(R)-l-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)- cyclopropanecarboxylic acid (Compound E); l-{4'-[4-((R)-l-Phenyl-ethoxycarbonylamino)- isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound F); (3-Methyl-5- {4'-[l-(5- oxo-2,5-dihydro-[l ,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)-l -phenyl-ethyl ester (Compound G); (3-Methyl-5- {4'-[l-(lH-tetrazol-5-yl)-cyclopropyl]- biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound H); or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof.

[0019] In some embodiments, the LPA1 receptor antagonist is formulated for topical administration, oral administration, or parenteral administration.

[0020] In some embodiments, the LPA1 receptor antagonist is systemically administered to the mammal.

[0021] In some embodiments, the LPA1 receptor antagonist is orally administered to the mammal.

[0022] In some embodiments, the LPA1 receptor antagonist is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.

[0023] In some embodiments, the LPA1 receptor antagonist is administered to the mammal by injection or intraveneously.

[0024] In some embodiments, the LPA1 receptor antagonist is topically administered to the mammal.

[0025] In some embodiments, the LPA1 receptor antagonist is topically administered to the mammal in the form of an ointment, cream, lotion, paste, gel, stick, a film, spray, a patch or wound dressing. [0026] In some embodiments, the method further comprises administereing to the mammal a therapeutically-effective amount of a second active agent.

[0027] In some embodiments, the method further comprises administereing to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppresants, analgesics, anti-inflammatories, chemokine receptor antagonists, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase Ai inhibitors, phospholipase A₂ inhibitors, lysophospholipase D (lysoPLD) inhibitors, and autotaxin inhibitors.

[0028] In some embodiments, provided herein is a topical formulation comprising an LPA1 receptor antagonist and at least one suitable pharmaceutically acceptable excipient, wherein the topical formulation is suitable for administration to the skin of a mammal. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist in an amount effective for the treatment of a dermal disease or condition. In some embodiments, the dermal disease or condition is a disease or condition as described herein. In some embodiments, the topical formulation is in the form of an ointment, cream, solution, lotion, paste, gel, stick, a film, a patch or wound dressing. In some embodiments, the topical formulation is in the form of an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist in an amount effective for the treatment of a dermal disease or condition and the topical formulation is in the form of an ointment, cream, solution, lotion, paste, gel, stick, a film, a patch or wound dressing.

[0029] In some embodiments, provided herein is a topical formulation comprising an LPA1 receptor antagonist in an amount effective for the treatment of a dermal disease or condition, and at least one suitable pharmaceutically acceptable excipient to provide an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing, wherein the topical formulation is suitable for

administration to the skin of a mammal.

[0030] In some embodiments, provided herein is a topical formulation comprising an LPA1 receptor antagonist in an amount effective for antagonizing dermal LPA receptors, and at least one suitable pharmaceutically acceptable excipient to provide an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing.

[0031] In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), or a pharmaceutically acceptable salt, prodrug, active metabolite, or a

pharmaceutically acceptable solvate thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (rV), or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of Formula (VI) or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises an LPA1 receptor antagonist that has a structure of or Formula (VII), or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the topical formulation comprises an LPA1 receptor antagonist, or a pharmaceutically acceptable salt thereof, disclosed in: US Provisional Application no. 61/122,568;

US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional

Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681 ; US Provisional Application no. 61/2472877; International patent application no.

PCT/US2010/44284; International patent application no. PCT/US2010/51199; International patent application no. PCT/US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786; International patent application no. PCT/US2010/50787; US

Patent Application no. 12/893,902; International patent application no. PCT/US09/68106;

International patent application no. PCT/US09/68105; International patent application no.

PCT/US09/67527; International patent application no. PCT/USlO/37309; International patent application no. PCT/USlO/37316; or US Patent Application no. 12/793,440; each of which is herein incorporated by reference.

[0033] In some embodiments, the topical formulation comprises (R)-2-(4'-(3-methyl-4-((l- phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A); (R)-l-(4'-(3- methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)cyclopropanecarboxylic acid (Compound B); (R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5- yl)biphenyl-4-yl)acetic acid (Compound C); {5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)- biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound D); 1- (4'- {4-[(R)-l-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)- cyclopropanecarboxylic acid (Compound E); l-{4'-[4-((R)-l-Phenyl-ethoxycarbonylamino)- isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound F); (3-Methyl-5- {4'-[l-(5- oxo-2,5-dihydro-[l ,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)-l -phenyl-ethyl ester (Compound G); or (3-Methyl-5-{4'-[l-(lH-tetrazol-5-yl)-cyclopropyl]- biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound H); or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof. [0034] LPA antagonists are suitable for treating a dermatological disease or condition (i.e., an abnormal state of the skin (e.g., epidermis, the dermis and/or the hypodermis)). Described herein, are formulations for treating an immune disorder or autoimmune disorder (e.g. an inflammtory disorder (e.g., scleroderma, eczema, psoriasis)); a proliferative disorder (e.g., melanoma); scarring, including e.g., keloids; a burn (e.g., fist degree, second degree, third degree, or fourth degree); a wound (e.g., a surgical wound); a fibrotic disease or condition; or combinations thereof. The formulations described herein include one or more LPA1 antagonists. Administration of the formulations described herein treats and/or prevents diseases or conditions in which the

physiological activity of LPA is involved in the etiology or pathology of the disease or condition, or is otherwise associated with at least one symptom of a disease or condition. In some embodiments, the administration is by systemic administration. In some embodiments, the administration is by topical administration.

[0035] Provided herein are topical formulations comprising an LPA1 antagonist in an amount effective for the treatment of a dermatological disorder. Provided herein are topical formulations comprising an LPA1 antagonist in an amount effective for the treatment of a dermatological disorder, and suitable excipients to provide an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing, wherein the formulation is in a form suitable for application to the skin of a mammal.

[0036] Also provided herein are topical formulations comprising an LPA receptor antagonist in an amount effective for antagonizing LPA receptors, and suitable excipients to provide an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing. In one aspect, provided herein is a topical formulation comprising an LPA receptor antagonist in an amount effective for antagonizing dermal LPA receptors, and at least one suitable pharmaceutically acceptable excipient to provide an ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing.

[0037] In some embodiments, the LPA receptor antagonist is an antagonist of one or more LPA receptors selected from LPAi, LPA₂, LPA₃, LPA₄ and LPA₅. In some embodiments, the LPA receptor antagonist is a selective LPAi antagonist. In some embodiments, the LPA receptor antagonist is a pan-LPA receptor antagonist.

[0038] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is scarring, dermatitis, a proliferative disease or condition, a fibrotic disease or condition, or an inflammatory disease or condition.

[0039] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is bullous disorders, collagenoses, psoriasis, psoriatic lesions, eczema, urticaria, rosacea, hypertrophic scarring, keloid scar formation, scleroderma, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma and/or melanoma. [0040] In some embodiments, the topical formulation comprises an LPA antagonist wherein the LPA antagonist is an antagonist of one or more LPA receptors selected from LPAi, LPA₂, LPA₃, LPA₄ and LPA₅. In some embodiments, the topical formulation comprises an LPA receptor antagonist wherein the LPA receptor antagonist is an antagonist of LPA_! .

[0041] In some embodiments, the formulation described herein comprises an LPA antagonist that is a selective LPAi antagonist.

[0042] Also provided herein is a method of treating of an LPA-dependent or LPA-mediated disease or condition, comprising administering to a mammal in need thereof a therapeutically-effective amount of a formulation described herein.

[0043] Also provided herein is a method of treating of an LPA-dependent or LPA-mediated disease or condition, comprising administering to a mammal in need thereof a therapeutically-effective amount of a topical formulation described herein.

[0044] Provided herein is a method of antagonizing dermal LPA receptors in a mammal in need thereof, comprising administering to the mammal a therapeutically-effective amount of a topical formulation described herein. In one aspect, the mammal has at least one symptom of an LPA- dependent or LPA-mediated dermatological disease or condition. In some embodiments, the mammal has at least one symptom of an LPAi -dependent or LPAi-mediated dermatological disease or condition.

[0045] In some embodiments of the methods described herein, the LPA-dependent or LPA- mediated disease or condition is scarring, dermatitis, a proliferative disease or condition, a fibrotic disease or condition or an inflammatory disease or condition.

[0046] In some embodiments of the methods described herein, the LPA-dependent or LPA- mediated disease or condition is bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, keloids, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma and/or melanoma.

[0047] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is scarring. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is hypertrophic scarring. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is a keloid scar. In some embodiments, the LPA-dependent or LPA-mediated disease or condition results from surgery. In some embodiments, the topical formulation is administered before surgery. In some embodiments, the topical formulation is administered after surgery.

[0048] Provided herein, in some embodiments, is a method of increasing the dermal concentration of a LPA receptor antagonist in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a topical formulation described herein. In some embodiments, the mammal has at least one symptom of an LPA-dependent or LPA-mediated dermatological disease or condition. In some embodiments, the mammal has at least one symptom of an LPAi- dependent or LPAi-mediated dermatological disease or condition.

[0049] In some embodiments of the methods described herein, the topical formulation is in the form of ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing, or combinations thereof.

[0050] In one aspect, dermal administration of any topical formulation described herein antagonizes dermal LPA receptors locally in the skin (e.g., the epidermis, the dermis and/or hypodermis).

Localized antagonism of dermal LPA receptors is preferred for diseases or conditions limited to the surface tissues of a mammal. In addition, localized antagonism of dermal LPA receptors avoids attenuation of beneficial effects of LPA in other parts of the body of an individual.

[0051] In some embodiments, compounds provided herein are administered to a human. In some embodiments, compounds provided herein are orally administered to a human. In some

embodiments, compounds provided herein are topically administered to a human.

[0052] In some embodiments, compounds provided herein are used as antagonists of at least one

LPA receptor. In some embodiments, compounds provided herein are used for inhibiting the activity of at least one LPA receptor or for the treatment of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPAi.

[0053] In other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of LPA i activity.

[0054] Articles of manufacture, which include packaging material, a formulation within the packaging material (e.g. a formulation suitable for topical administration), and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, used for inhibiting the activity of at least one LPA receptor, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor, are provided.

[0055] Other objects, features and advantages of the topical formulations described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF FIGURES

[0056] FIGURE 1 illustrates the results of Compound A on dermal thickness in a mouse model of bleomycin-induced scleroderma.

[0057] FIGURE 2 illustrates the results of Compound A on collagen content in a mouse model of bleomycin-induced scleroderma.

[0058] FIGURE 3 illustrates the results of Compound B on dermal thickness in a mouse model of bleomycin-induced scleroderma.

[0059] FIGURE 4 illustrates the results of Compound B on collagen content in a mouse model of bleomycin-induced scleroderma.

DETAILED DESCRIPTION OF THE INVENTION

[0060] Lysophospholipids (such as lysophosphatidic acid (LPA)) affect fundamental cellular functions that include cellular proliferation, differentiation, survival, migration, adhesion, invasion, and morphogensis. These functions influence many biological processes that include neurogensis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0061] LPA acts through sets of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion. LPA binding to its cognate GPCRs (LPA LPA₂, LPA₃, LPA₄, LPA₅, LPA₆) activates intracellular signaling pathways to produce a variety of biological responses.

[0062] LPA has a role as a biological effector molecule, and has a diverse range of physiological actions such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. The effects of LPA are predominantly receptor mediated.

[0063] Activation of the LPA receptors with LPA mediates a range of downstream signaling cascades. The actual pathway and realized end point are dependent on a range of variables that include receptor usage, cell type, expression level of a receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, tissues and organs co-express several LPA-receptor subtypes, which indicates that LPA receptors signal in a cooperative manner. LPAi, LPA₂, and LPA₃ share high amino acid sequence similarity.

[0064] Activation of the LPA receptors (LPAi, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆) with LPA mediates a range of downstream signaling cascades. These include, but are not limited to, mitogen- activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C (PLC) activation/Ca²⁺ mobilization, arachidonic acid release, Akt/PKB activation, and the activation of small GTPases, Rho, ROCK, Rac, and Ras. Other pathways that are affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42/GTP -binding protein (Cdc42) , proto-oncogene serine/threonine-protein kinase

Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation,

phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RACl). The actual pathway and realized end point are dependent on a range of variables that include receptor usage, cell type, expression level of a receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, tissues and organs co-express several LPA-receptor subtypes, which indicates that LPA receptors signal in a cooperative manner.

[0065] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Fibroblast proliferation is required in wound healing in order to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can either increase or suppress the proliferation of cell types important in wound healing.

[0066] Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue structure and function. If not, these responses can lead to tissue fibrosis and loss of function.

[0067] A number of muscular dystrophies are characterized by a progressive weakness and wasting of musculature, and by extensive fibrosis. It has been shown that LPA treatment of cultured myoblasts induced significant expression of connective tissue growth factor (CTGF). CTGF subsequently induces collagen, fibronectin and integrin expression and induces dedifferentiation of these myoblasts. Treatment of a variety of cell types with LPA induces reproducible and high level induction of CTGF. CTGF is a profibrotic cytokine, signaling down-stream and in parallel with TGF .

[0068] Normal wound healing (e.g. dermal repair) occurs by a highly coordinated sequence of events in which cellular, soluble factors and matrix components act in concert to repair the injury. The healing response can be described as taking place in four broad, overlapping phases— hemostasis, inflammation, proliferation, and remodeling. Many growth factors and cytokines are released into a wound site (e.g., a blister, a scar, a keloid, a melanoma, an allergic rash, psoriatic lesions) to initiate and perpetuate wound healing processes.

[0069] At the site of a wound, damaged blood vessels activate platelets. Activated platelets release bioactive mediators to induce cell proliferation, cell migration, blood coagulation, and angiogenesis. LPA is one such mediator that is released from activated platelets; this induces platelet aggregation along with mitogenic/migration effects on the surrounding cells, such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes. [0070] Topical application of LP A to cutaneous wounds in mice promotes repair processes (wound closure and increased neoepithelial thickness) by increasing cell proliferation/ migration without affecting secondary inflammation.

[0071] In some embodiments, LPAI antagonists do not change wound healing when administered to a mammal. In one embodiment, the effects of Compound A on wound healing in mice and rats was examined, wherein Compound A was administered to mice and rats prior to and after a single incisional wound and a single exicisional wound was made on the back of each animal. In this study, daily (rats) or twice daily (mice) administration of Compound A (30 mg/kg) did not change wound healing in either species tested following incisional or excisisioanl wounds.

[0072] Activation of dermal fibroblasts by growth factors and cytokines leads to their subsequent migration from the edges of the wound into the provisional matrix formed by the fibrin clot whereupon the fibroblasts proliferate and start to repair the wound by secreting and organizing the characteristic dermal extracellular matrix (ECM). The increasing number of fibroblasts within the wound and continuous precipitation of ECM enhances matrix rigidity by applying small tractional forces to the newly formed granulation tissue. The increase in mechanical stress, in conjunction with transforming growth factor β (TGFP), induces a-smooth muscle actin (a-SMA) expression and the subsequent transformation of fibroblasts into myofibroblasts. Myofibroblasts facilitate granulation tissue remodeling via myofibroblast contraction and through the production of ECM components and thus mediate wound repair.

[0073] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Connective tissue growth factor (CTGF) is a profibrotic cytokine and is involved in the development and maintenance of fibrosis and excessive scarring. LPA increases the expression of CTGF and alters the morphology of human dermal scars (e.g. keloids) by modulating the activity of dermal fibroblasts. In one apsect, LPA receptor antagonists decrease CTGF expression and prevent excessive scarring and fibrotic disorders.

[0074] Fibroblast proliferation is required in wound healing in order to fill an open wound. In contrast, fibrosis, scarring, dermal inflammatory disorders (e.g. psoriasis) and/or dermal proliferation disorders (e.g., melanoma) are characterized by aberrant proliferation and/or accumulation of myofibroblasts and/or deposition of collagen. Any dermal disease or condition initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue (e.g. skin (e.g., the epidermis, the dermis and/or hypodermis) structure and function. If not, these responses can lead to tissue fibrosis and/or scarring.

[0075] A role for LPAi in LPA-induced proliferation was provided by the observation that LPA- stimulated proliferation of fibroblasts isolated from LPAi receptor null mice was attenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes that are integral to fibroblast adhesion, migration, differentiation and contraction. [0076] Lysophospho lipid signaling plays a role in the development and maturation of blood vessels. Angiogenesis, the formation of new capillary networks from pre-existing vasculature, is normally invoked in wound healing, tissue growth and myocardial angiogenesis after ischemic injury. Peptide growth factors (e.g. vascular endothelial growth factor (VEGF)) and lysophospholipids control coordinated proliferation, migration, adhesion, differentiation and assembly of vascular endothelial cells (VECs) and surrounding vascular smooth-muscle cells (VSMCs). In one aspect, dysregulation of the processes mediating angiogenesis leads to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis.

[0077] Dysfunction of the vascular endothelium can shift the balance from vasodilatation to vasoconstriction and lead to hypertension and vascular remodeling.

Fibrosis

[0078] Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue structure and function. If not, these responses can lead to tissue fibrosis and loss of function.

[0079] For the majority of organs and tissues the development of fibrosis involves a multitude of events and factors. Molecules involved in the development of fibrosis include proteins or peptides (profibrotic cytokines, chemokines, metalloproteinases etc.) and phospholipids. Phospholipids involved in the development of fibrosis include platelet activating factor (PAF), phosphatidyl choline, sphingosine- 1 phosphate (SIP) and lysophosphatidic acid (LP A).

[0080] LPA and LPAi play pathogenic roles in skin fibrosis. It has been shown that the levels of LPA are significantly higher in the serum of systemic sclerosis subjects as compared to control subjects (Tokumura, A., et al. 2009. Int JMed Sci 6: 168-176). It has also been shown that injured human skin contains increased amounts of both LPA and cells expressing LPA_t (Mazereeuw- Hautier, J., et al., 2005. J Invest Dermatol 125:421-427).

[0081] In one aspect, an LPAl receptor antagonist is used to treat or prevent dermal fibrosis in a mammal. In one aspect, the dermal fibrosis is a symptom of an autoimmune disorder. In one aspect is a method for preventing a dermal fibrosis condition in a mammal, the method comprising administering to the mammal at risk of developing one or more dermal fibrotic conditions a therapeutically effective amount of a LPAl receptor antagonist. In one aspect, the mammal has been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of dermal tissues. In some embodiments, the mammal has a genetic predisposition of developing dermal fibrosis. In some embodiments, a LPAl receptor antagonist is adminstered to a mammal to prevent or minimize scarring following injury. In one aspect, injury includes surgery.

[0082] The terms "fibrosis" or "fibrosing disorder," as used herein, refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

[0083] Exemplary diseases, disorders, or conditions that involve dermal fibrosis include, but are not limited to: scleroderma, head and neck fibrosis, e.g., radiation induced; hypertrophic scarring and keloids, e.g., burn induced or surgical; mixed connective tissue disease.

[0084] In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions will benefit from therapy with a LPAl receptor antagonist:

vasculitis (e.g. cutaneous vasculitis, livedoid vasculitis), formation of scar tissue, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts.

[0085] In one aspect, a LPAl receptor antagonist is adminstered to a mammal with dermal fibrosis or with a predisposition of developing dermal fibrosis with one or more other agents that are used to treat fibrosis. In one aspect, the one or more agents include corticosteroids. In one aspect, the one or more agents include immunosuppresants. In one aspect, the one or more agents include B-cell antagonists. In one aspect, the one or more agents include uteroglobin.

[0086] In some embodiments, provided is a method of reducing dermal tissue injury, dermal vascular leakage, inflammation and/or fibrosis in a mammal comprising administering to the mammal a selective LPAl receptor antagonist. In some embodiments, provided is a method of reducing dermal injury, dermal vascular leakage, inflammation and fibrosis in a mammal comprising administering to the mammal a selective LPAl receptor antagonist. In some embodiments, provided is a method of attenuating dermal fibrosis in a mammal comprising administering a selective LPAl receptor antagonist. In some embodiments, provided is a method of attenuating dermal tissue remodeling and fibrosis in a mammal comprising administering a selective LPAl receptor antagonist.

[0087] Vascular leak refers to an increase in vascular permeability due to tissue injury. Such a condition may result in internal bleeding and blood coagulation, inflammation, and ultimately the development of fibrosis. Tissue injury is usually associated with increased vascular permeability. It has been reported that release of bioactive mediators (e.g. LP A) may be responsible for increased vascular permeability (Dvorak, H. F., N Engl J Med 315: 1650-1659, 1986; van Nieuw Amerongen et al., Arterioscler Thromb Vase Biol 20:E127-E133, 2000).

[0088] In some embodiments, provided is a method of reducing myofibroblast accumulation in dermal tissues of a mammal comprising administering a LPAl receptor antagonist to the mammal. In some embodiments, provided is a method of reducing TGF-β activation in dermal tissues of a mammal comprising administering a LPAl receptor antagonist to the mammal. In some embodiments, provided is a method of reducing TGF-β signaling in dermal tissues of a mammal comprising administering a LPAl receptor antagonist to the mammal. [0089] In some embodiments, provided is a method of decreasing cytokine production in a mammal comprising administering a selective LPAl receptor antagonist. In some embodiments, the method of decreasing cytokine production in a mammal comprising administering a selective LPAl receptor antagonist results in a reduction of dermal tissue damage and dermal fibrosis in a mammal.

[0090] In some embodiments, provided is a method of treating dermal fibrosis is a mammal comprising administering to the mammal a selective LPAl receptor antagonist. In some embodiments, provided is a method of treating fibrosis in a mammal while maintaining body weight in the mammal comprising administering to the mammal a selective LPAl receptor antagonist.

[0091] In some embodiments, provided is a method of treating fibrosis in a mammal with a selective LPAl receptor anatgonist, wherein the fibrosis in the mammal is not responsive to treatment with pirfenidone.

[0092] As shown in the Examples, a selective LPAl receptor antagonist reduced dermal thickening and collagen content in a bleomycin mouse model of scleroderma. In this model, tissue injury produced by repeated subcutaneous injections of bleomycin results in dermal fibrosis with histopathological changes resembling those seen in scleroderma, including the deposition of collagen and other extracellular matrix components and the accumulation of fibroblasts and myofibroblasts. The sustained activation of fibroblast TGF- /Smad Signaling has been observed in the bleomycin mouse model J Invest Dermatol 121 :41-50; 2003).

[0093] In one aspect, a LPA receptor antagonist (e.g. a LPAl receptor antagonist) is used to treat a dermatological disorder in a mammal.

[0094] Disclosed herein, in certain embodiments, are formulations for treatment of dermatological disorders. In some embodiments, the dermatological disorder is characterized by undesired/abnormal fibrosis.

[0095] The term "dermatological disorder," as used herein refers to a skin disorder. Such dermatological disorders include, but are not limited to, fibrotic, proliferative and/or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

[0096] As used herein, the terms "dermatological disease or condition" and "dermal disease or condition" are used interchangeably and include any abnormal state of the skin, including the epidermis, dermis and/or hypodermis.

[0097] As used herein, the term "dermal" include outer and inner layers of the skin including the epidermis, the dermis, and/or the hypodermis. The epidermis forms the first layer of skin and contains no blood vessels. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. The dermis is the layer of skin beneath the epidermis and consists of connective tissue. The dermis is tightly connected to the epidermis by a basement membrane and contains hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The hypodermis lies below the dermis and attaches the outer skin layers to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue and elastin. The main cell types in the hypodermis are fibroblasts, macrophages and adipocytes (subcutaneous adipose layer).

[0098] Disclosed herein is the use of LPA antagonists in the treatment of diseases or conditions affecting dermal tissues.

[0099] In certain instances, a dermatological disorder is caused by an immune disease or condition, an inflammatory disease or condition, a proliferative disease or condition, an overproduction of sebum lipids, a fibroblast disease or condition (e.g., scarring), a burn, a fibrotic disease or condition, or combinations thereof. In some instances a dermatological disease or condition is a chronic blistering (bullous) disorder, acne, psoriasis, dermatitis (e.g., contact or atopic), eczema, urticaria, rosacea, scarring (i.e. the formation of a scar (e.g., a keloid scar or a hypertrophic scar)), a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, or melanoma.

Dermatological diseases or conditions include, but are not limited to, atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, scarring, hypertrophic scarring, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren- Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma, and melanoma.

[00100] In some embodiments, a topical formulation disclosed herein is administered before or after contact with an allergen and/or irritant. In some embodiments, a topical formulation disclosed herein is administered before or after a physical trauma (e.g., surgery). In some embodiments, a topical formulation described herein is administered to an individual suspected of having an LPA-dependent or LPA-mediated dermal disease or condition. In some embodiments, a topical formulation described herein is administered to an individual diagnosed with an LPA-dependent or LPA- mediated dermal disease or condition.

Inflammation

[00101] LPA has been shown to regulate immunological responses by modulating activities/functions of immune cells such as T-/B-lymphocytes and macrophages. In activated T cells, LPA activates IL- 2 production/cell proliferation through LPAi. Expression of LPA-induced inflammatory response genes is mediated by LPAi and LPA₃ (Biochem Biophys Res Commun. 363(4): 1001-8, 2007). In addition, LPA modulates the chemotaxis of inflammatory cells {Biochem Biophys Res Commun., 1993, 15;193(2), 497). The proliferation and cytokine-secreting activity in response to LPA of immune cells, platelet aggregation activity in response to LPA, acceleration of migration activity in monocytes, activation of NF-κΒ in fibroblast, enhancement of fibronectin-binding to the cell surface, and the like are known. Thus, LPA is associated with various inflammatory/immune diseases.

[00102] LPA is associated with various inflammatory/immune diseases. In one aspect, a LPA1 antagonist is used to treat or prevent inflammation in a mammal. In one aspect, antagonists of LPA_! and/or LP A3 find use in the treatment or prevention of inflammatory/immune disorders in a mammal.

[00103] Examples of inflammatory/immune disorders include psoriasis, vasculitis, dermatitis, inflammatory muscle disease, scleroderma, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, dermatomyositis.

[00104] In certain aspects, are methods for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an effective amount of a LPA1 antagonist.

Scleroderma

[00105] Scleroderma or systemic sclerosis is a potentially fatal autoimmune disease of unknown etiology, characterized by progressive multi-organ fibrosis that is largely refractory to currently available pharmacological therapies. Systemic sclerosis is thought to be initiated by tissue injury, in response to which dysregulated wound-healing processes are thought to contribute to the development of fibrosis. Mediators driving aberrant or over-exuberant wound-healing responses in this disease include LPAi and LPA.

[00106] In some embodiments, it has been observed that the levels of LPA are significantly higher in the serum of systemic sclerosis subjects versus controls, indicating that LPA is involved in the pathogenesis of systemic sclerosis (Int JMed Sci 6: 168-176, 2009).

[00107] In some embodiments, a formulation disclosed herein is used to treat scleroderma. There are two major forms of scleroderma: limited systemic sclerosis (also known as morphea or cutaneous scleroderma) and diffuse systemic sclerosis. In some embodiments, a formulation disclosed herein is used to treat limited systemic sclerosis. In some embodiments, a formulation disclosed herein is used to treat diffuse systemic sclerosis.

[00108] In some cases scleroderma runs in families. Thus, in some embodiments, a formulation disclosed herein is administered prophylactically to asymptomatic members of a family wherein at least one member of the family has been diagnosed with scleroderma.

[00109] In some embodiments, scleroderma is a manifestation of another disease or condition. In such individuals who are diagnosed with the other disease or condition, a formulation disclosed herein is administered prophylactically to prevent the onset of scleroderma. Limited Systemic Scleroderma

[00110] As used herein, "limited systemic scleroderma" means a disorder characterized by the thickening and hardening of the skin and subcutaneous tissues from excessive collagen deposition. It is often accompanied by the following: calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias. Additionally, an individual suffering from limited systemic sclerosis may present with pulmonary arterial hypertension.

[00111] As used herein, "calcinosis" means a disorder characterized by the formation of calcium deposits in soft tissue. In some embodiments, a formulation disclosed herein is administered to treat calcinosis. In some embodiments, a formulation disclosed herein is administered to treat limited systemic scleroderma, wherein the individual in need thereof presents with calcinosis.

Diffuse Systemic Scleroderma

[00112] As used herein, "diffuse systemic scleroderma" means a disorder of the skin and internal organs characterized by the thickening and hardening of the skin and subcutaneous tissues from excessive collagen deposition. In certain instances, diffuse systemic scleroderma is accompanied by Raynaud's phenomenon and calcinosis. In some embodiments, a formulation disclosed herein is administered to treat diffuse systemic scleroderma, wherein the individual in need thereof presents with Raynaud's phenomenon. In some embodiments, a formulation disclosed herein is administered to treat diffuse systemic scleroderma, wherein the individual in need thereof presents with calcinosis.

[00113] In some embodiments, a LPA1 receptor antagonist is used in the treatment or prevention of any one of the following in a mammal: localized cutaneous scleroderma, localized morphea, morphea- lichen sclerosus et atrophicus overlap, generalized morphea, atrophoderma of Pasini and Pierini, pansclerotic morphea, morphea profunda, linear scleroderma, systemic scleroderma, CREST syndrome, sclerodactyly, systemic sclerosis, progressive systemic sclerosis.

Raynaud's phenomenon

[00114] In one aspect, compounds disclosed herein are used to treat Raynaud's phenomenon.

Raynaud's phenomenon comprises both Raynaud's disease (where the phenomenon is idiopathic) and Raynaud's syndrome, where it is caused by some instigating factor. Raynaud's phenomenon means a disorder characterized by discoloration of the fingers, toes, and occasionally other areas.

[00115] Raynaud's phenomenon is an exaggeration of vasomotor responses to cold or emotional stress. It is a hyperactivation of the sympathetic system causing extreme vasoconstriction of the peripheral blood vessels, leading to tissue hypoxia. Chronic, recurrent cases of Raynaud

phenomenon can result in atrophy of the skin, subcutaneous tissues, and muscle. In some cases it can cause ulceration and ischemic gangrene.

[00116] Raynaud's phenomenon is the initial symptom that presents for 70% of patients with scleroderma. In some embodiments, a formulation disclosed herein is administered to treat

Raynaud's phenomenon. In some embodiments, a formulation disclosed herein is administered to treat limited systemic scleroderma, wherein the individual in need thereof presents with Raynaud's phenomenon.

[00117] In one aspect, provided herein are methods for preventing or treating vasoconstriction, or vasculitis in a mammal comprising administering at least once to the mammal an effective amount of a LPA1 receptor antagonist.

[00118] In one aspect, provided herein are methods for reducing the constriction of blood vessels in a mammal comprising administering at least once to the mammal an effective amount of a LPA1 receptor antagonist.

Dupuytren's disease

[00119] In some embodiments, a formulation disclosed herein is administered to treat or prevent

Dupuytren's disease. Dupuytren's disease is a disease wherein the tissues under the skin on the palm of the hand thicken and shorten so that the tendons connected to the fingers cannot move freely. It is characterized by fixed flexion contracture of the hand. Dupuytren's disease results from abnormal fibrosis of the palmar fascia.

Capsular Contracture

[00120] In some embodiments, a formulation disclosed herein is administered to a mammal to treat or prevent capsular contracture. Capsular contracture is an abnormal response of the immune system to foreign materials. When breast implants, or any other foreign object, such as artificial joint prosthetics, are placed in the body, the body forms a lining around it. Capsular contracture is characterized by the formation of capsules of collagen fibers around a foreign body. In certain instances, capsular contracture results from an abnormal immune response to breast implants and artificial joint prosthetics. In some embodiments, a formulation disclosed herein is administered before, during, or concurrently with breast augmentation. In some embodiments, a formulation disclosed herein is administered before, during, or concurrently with the implantation of an artificial joint.

Retroperitoneal Fibrosis

[00121] In some embodiments, a formulation disclosed herein is administered to treat or prevent retroperitoneal fibrosis. Retroperitoneal fibrosis is a disorder in which the tubes (ureters) that carry urine from the kidneys to the bladder are blocked by a mass in the area behind the stomach and intestines. As used herein, "retroperitoneal fibrosis" means an immune disorder characterized by the proliferation of fibrous tissue in the retroperitoneum.

Cutaneous Radiation Syndrome

[00122] In some embodiments, a formulation disclosed herein is administered to treat cutaneous radiation syndrome. As used herein, "cutaneous radiation syndrome" means the pathophysiological reactions of the skin and skin appendages to significant levels of ionizing radiation. In certain instances, an individual with cutaneous radiation syndrome presents with abnormal skin fibrosis. In some embodiments, a formulation disclosed herein is used to treat cutaneous radiation syndrome, wherein an individual in need thereof present with undesired/abnormal skin fibrosis.

Bullous Disorders

[00123] It has been shown that LPA was present in the blister fluids of patients with multiple different bullous dermatoses at concentrations higher than in their plasma, and that expression levels of LPAi as well as the LPA-synthesizing enzyme autotaxin were greatly increased in blistered versus normal skin. In some embodiments, a topical formulation disclosed herein is administered to treat a bullous disease or condition. In certain instances, a bullous disease or condition is characterized by the formation of blisters (i.e., the accumulation of fluid between cells in the upper layers of the skin (e.g., the dermis and/or epidermis)). Bullous diseases or conditions include, but are not limited to, bullous pemphigoid, pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceous, paraneoplastic pemphigus, mucous membrane pemphigoid, linear IgA bullous disease, dermatitis herpeti-formis, and epidermolysis bullosa acquisita. In certain instances, the expression of LPA-induced inflammatory response genes of immune cells such as T-/B-lymphocytes, endothelial cells and macrophages is mediated by LPAi and/or LPA₃ {Biochem Biophys Res Commun. ;363(4): 1001-8). In one aspect the topical formulations described herein reduce, ameliorate or inhibit the LPA-induced inflammatory response of immune cells associated with bullous disorders. In one aspect, antagonism of dermal LPA receptors reduces, ameliorates or inhibits the LPA-induced inflammatory response of immune cells. In one aspect, the LPA receptors are LPAi and/or LP A3 receptors. In one aspect the LPA receptors are LPAi receptors.

Skin Cancer

[00124] Lysophospholipid receptor signaling plays a role in the etiology of cancer. LPA and LPAi, LPA₂, and/or LPA₃ play a role in the development of several types of cancers. The initiation, progression and metastasis of cancer involve several concurrent and sequential processes including cell proliferation and growth, survival and anti-apoptosis, migration of cells, penetration of foreign cells into defined cellular layers and/or organs, and promotion of angiogenesis. The control of each of these processes by LPA signaling in physiological and pathophysiological conditions underscores the potential therapeutic usefulness of modulating LPA signaling pathways for the treatment of cancer. LPA signals through its own GPC s leading to activation of multiple downstream effector pathways. Such downstream effector pathways play a role in cancer. LPA and its GPCRs are linked to cancer through major oncogenic signaling pathways.

[00125] LPA contributes to tumorigenesis by increasing motility and invasiveness of cells.

[00126] The cellular responses to LPA are mediated through the lysophosphatidic acid receptors.

[00127] In one aspect, a LPAI antagonist is used in the treatment of cancer. In one aspect, a LPAI antagonist is used in the treatment of malignant and benign proliferative diseases affecting dermal tissues. In one aspect, a LPAI receptor antagonist is used to prevent or reduce proliferation of tumor cells, invasion and metastasis of dermal cancers. In one aspect is a method of treating cancer in a mammal, the method comprising administering to the mammal a LPA1 antagonist and a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[00128] In some embodiments, a formulation disclosed herein is administered to treat a dermal cancer. Dermal cancers include melanoma, squamous cell carcinoma and basal cell carcinoma. In certain instances, inflammation facilitates the growth of dermal cancers. In certain instances, LPA mediates inflammation associated with dermal cancer. In certain instances, antagonizing LPA receptors reduces inflammation and/or proliferation associated with dermal cancers, and slows and/or inhibits the growth of cells (e.g., melanocytes, fibroblasts) associated with dermal cancers.

[00129] In one aspect, a LPA1 receptor antagonist reduces, ameliorates or inhibits cell proliferation and/or fibrosis associated with cancers. In one aspect, antagonizing dermal LPA receptors treats dermatological cancers. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

[00130] The term "cancer," as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer include, but are not limited to, melanoma, cutaneous T cell lymphoma, mycosis fungoides, Merkel cell carcinomas, head and neck carcinomas, solar keratosis, squamous cell or basal cell cancer at any stage of the disease with or without metastases.

Psoriasis

[00131] In some embodiments, a topical formulation disclosed herein is administered to treat psoriasis. In certain instances, the expression of LPA-induced inflammatory response genes of immune cells such as T-/B-lymphocytes, endothelial cells and macrophages is mediated by LPAi and/or LPA₃ (Biochem Biophys Res Commun. ;363(4): 1001-8). The proliferating cells in psoriatic skin comprise T-cells and/or endothelial cells {Journal of Investigative Dermatology (1991) 96, 333- 340). In certain instances, LPA mediates inflammation associated with psoriasis by inducing the expression of inflammatory response genes in immune cells. In certain instances, antagonizing dermal LPA receptors reduces inflammation associated with psoriasis. In certain instances, antagonizing LPA receptors treats poriasis and psoriatic lesions. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

Dermatitis

[00132] In some embodiments, a topical formulation disclosed herein is administered to treat dermatitis. As used herein, dermatitis means an inflammatory condition of the skin. In certain instances, dermatitis is acute and results from contact with an offending agent (e.g., uruishol). In certain instances, dermatitis is chronic and results from hypersensitivity. In certain instances, the symptoms of dermatitis (e.g., chronic or acute) result from a disorder of an immune system. In certain instances, the expression of LPA-induced inflammatory response genes of immune cells such as T-/B-lymphocytes, endothelial cells and macrophages is mediated by LPAi and/or LPA₃ {Biochem Biophys Res Commun. ;36 (4): 1001-8). In addition, LPA modulates the chemotaxis of inflammatory cells (Biochem Biophys Res Commun., 1993, 15; 193(2), 497) and the proliferation and cytokine-secreting activity of immune cells associated with dermatitis ( J. Imuunol. 1999, 162, 2049). In certain instances, antagonizing LPA receptors reduces inflammation associated with dermatitis. In certain instances, antagonizing dermal LPA receptors treats inflammation associated with dermatitis. In certain instances, antagonizing dermal LPA receptors treats dermatitis and/or lesions associated with dermatitis. In one aspect, the dermatitis is chronic or acute. In one aspect, the dermatitis is atopic or contact dermatitis. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

Eczema

[00133] In some embodiments, a topical formulation disclosed herein is administered to a mammal to treat eczema. As used herein, eczema is a chronic inflammatory state of the skin. In certain instances, the symptoms of eczema result from an immune disorder. In some instances, symptoms of eczema result from contact with an allergen. In some instances, skin-selective T cell homing and activation, and dysregulated apoptosis of immune cells such as T cells, eosinophils, and

keratinocytes plays a role in eczematous disorders. In certain instances, LPA modulates the proliferation and cytokine secreting activity of immune cells. In certain instances, antagonizing LPA receptors reduces cytokine secreting activity of immune cells and consequent inflammation associated with eczema. In certain instances, antagonizing LPA receptors treats inflammation associated with eczema. In certain instances, antagonizing dermal LPA receptors treats itching and/or lesions associated with eczema. In one aspect, the eczema is allergic eczema. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

Urticaria

[00134] In some embodiments, a formulation disclosed herein is administered to a mammal to treat urticaria . In certain instances, urticaria results from hypersensitivity or another immune disorder. In some instances, symptoms of urticaria result from contact with an allergen. In some instances, skin- selective T cell homing and activation, and dysregulated apoptosis of immune cells such as T cells, eosinophils, and keratinocytes plays a role in urticaria. In certain instances, LPA modulates the proliferation and cytokine secreting activity of immune cells. In certain instances, antagonizing LPA receptors reduces cytokine secreting activity of immune cells and consequent inflammation associated with urticaria. In certain instances, antagonizing LPA receptors treats inflammation associated with urticaria. In certain instances, antagonizing dermal LPA receptors treats hives and/or lesions associated with urticaria. In one aspect, the urticaria is allergic urticaria. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are

LPAi receptors.

Rosacea

[00135] In some embodiments, a formulation disclosed herein is administered to a mammal to treat rosacea. Rosacea refers to any of erythematotelangiectatic rosacea (ETR), Papulopustular rosacea, and/or Phymatous rosacea. In certain instances, antagonizing LPA receptors treats rosacea. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

Scarring

[00136] In some embodiments, a formulation disclosed herein is administered to a mammal to treat scarring. As used herein, scarring refers to the formation of a scar. In one aspect, the scar is a hypertrophic scar, or keloid scar, or a scar resulting from acne. In certain instances, a scar is an area of fibrous tissue that results from the overproduction of collagen. In certain instances, wound healing comprises the migration of fibroblasts to the site of injury. In certain instances, fibroblasts deposit collagen. In certain instances, fibroblasts deposit excess collagen at the wound site, resulting in a scar.

[00137] In some embodiments, scarring results from a trauma (e.g., surgery). In some embodiments, a formulation disclosed herein is administered before, after, or concurrently with a surgery.

[00138] In some embodiments, the scarring results from a burn. In some embodiments, a formulation disclosed herein is administered while an individual is being treated for a burn.

[00139] In some embodiments, a formulation disclosed herein is administered before, after, or concurrently with a scar revision procedure.

[00140] In certain instances, LPA induces expression of connective tissue growth factor (CTGF) from fibroblasts; CTGF subsequently induces collagen, fibronectin and integrin expression. In certain instances, antagonizing LPA receptors reduces collagen deposition. In certain instances, antagonizing dermal LPA receptors inhibits the activity of and/or migration of fibroblasts associated with scarring. In certain instances, antagonizing LPA receptors treats scars. In one aspect, the scarring is keloids. In one aspect, the scarring is Folliculitis keloidalis nuchae. In one aspect, the scarring is due to a skin cancer, acne, eczema and/or psoriasis. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

Burns and surgical wounds

[00141] In some embodiments, a topical formulation disclosed herein is topically administered to a mammal to treat a burn or a surgical wound. As used herein, a burn refers to an injury to or the destruction of skin caused by heat, cold, electricity, chemicals, light, radiation, or friction. In one aspect, the burn is a first degree burn, a second degree burn, a third degree burn, or a fourth degree burn. In certain instances, a burn results in the formation of a scar. In certain instances, a burn results in inflammation. In certain instances, antagonizing LPA receptors inhibits the activity (e.g.cytokine secretion) and/or migration of immune cells associated with scarring and/or inflammation in the burn area. In certain instances, antagonizing dermal LPA receptors treats scarring and/or inflammation in the burn area. As used herein, a surgical wound refers to an injury to the skin assoicated with invasive surgery. In one aspect, antagonizing LPA receptors promotes healing of the surgical wound and/or scarring in the affected area of the surgical incision. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the LPA receptors are LPAi receptors.

[00142] In one aspect, the formulations described herein are used to treat dermatological disorders in a mammal. Exemplary dermatological disorders include, but are not limited to, wounds, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, scarring, hypertrophic scarring, scleroderma, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma and melanoma. In some embodiments, the topical formulations described herein reduce scarring associated with surgical wounds and/or reduce incidence of lesions due to inflammatory conditions.

[00143] In one aspect, the formulations described herein are used in the treatment of various dermal diseases or conditions associated with LPA, which include aberrant wound healing, inflammation, cell proliferation, collagen deposition and/or dermal fibrosis. In some embodiments, the formulations described herein are topically administered to a mammal and antagonize dermal LPA receptors in the mammal. In some embodiments, the formulations described herein are systemically

administered (e.g. oral, parenteral). In some instances, antagonizing LPA receptors that are associated with aberrant wound healing, inflammation, cell proliferation, collagen deposition and/or dermal fibrosis reduces or inhihbits the proliferation and/or motility and/or adhesion of fibroblasts and/or immune cells, and/or increases apoptosis of fibroblasts and/or immune cells associated with dermatological disorders. In one aspect the topical formulations described herein treat LPA- dependent or LPA-mediated dermal diseases or conditions. In one aspect, the dermal LPA receptors are LPAi and/or LPA₃ receptors. In one aspect the dermal LPA receptors are dermal LPAi receptors.

[00144] In one aspect, topical dermal administration of the formulations described herein reduces, or ameliorates pain associated with inflammation and/or proliferation, (e.g., muscle or joint pain; or pain due to wounds, scars, burns or blisters).

[00145] In certain aspects, the activity of dermal LPAi receptors in a mammal is directly or indirectly modulated by the administration of (at least once) a therapeutically effective amount of a topical formulation described herein. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi. In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of a topical formulation described herein. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of at least one dermal LPA receptor. In one aspect, the at least one dermal LPA receptor is LPA^

[00146] In accordance with one aspect, are methods for treating, preventing, reversing, halting or slowing the progression of LPA-dependent or LPA-mediated diseases or conditions once it becomes clinically evident, or treating the symptoms associated with or related to LPA-dependent or LPA- mediated diseases or conditions, by administering to the mammal a LPA1 antagonist. In certain embodiments, the subject already has a LPA-dependent or LPA-mediated disease or condition at the time of administration, or is at risk of developing a LPA-dependent or LPA-mediated disease or condition.

[00147] In accordance with one aspect, methods described herein include the diagnosis or determination of whether or not a patient is suffering from a LPA-dependent or LPA-mediated disease or condition by administering to the subject a therapeutically effective amount of a LPA1 antagonist and determining whether or not the patient responds to the treatment.

LPA1 Receptor Antagonists

[00148] In some embodiments, the LPA1 receptor antagonist is a a small molecule compound ("compound"), peptide, polypeptides, a peptidomimetics, proteins, an antibody, antibody ligand binding domains, an aptamer, or an oligonucleotide.

Compounds

[00149] In certain aspects, the activity of LPA_t in a mammal is directly or indirectly modulated by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi. In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of an LPA receptor. In one aspect, the LPA receptors are LPAi and/or LPA₃ receptors. In one aspect, the LPA receptors are LPAi and/or LPA₂ receptors

[00150] LPAi receptor antagonists are disclosed herein or in any one of the following: US

Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent

Application no. 12/638,702; US Provisional Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681; US Provisional Application no.

61/2472877; International patent application no. PCT/US2010/44284; International patent application no. PCT/US2010/51199; International patent application no. PCT/US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786;

International patent application no. PCT/US2010/50787; US Patent Application no. 12/893,902; International patent application no. PCT/US09/68106; International patent application no.

PCT/US09/68105; International patent application no. PCT/US09/67527; International patent application no. PCT/USlO/37309; International patent application no. PCT USlO/37316; US Patent Application no. 12/793,440; each of which is herein incorporated by reference.

[00151] In some embodim e of Formula (I):

wherein

R¹ is -C0₂H, -C0₂R^D, tetrazolyl, 5-oxo-2,5-dihydro-[l ,2,4]oxadiazol-3-yl, -

C(=0)NHS0₂CH₃, or -C(=0)NHS0₂CH₂CH₃; R^Dis -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, - CH(CH₃)₂, -CH₂CH₂CH₂CH₃ , or -C(CH₃)₃ ;

L¹ is Ci-C₄alkylene or C₃-C₆cycloalkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃;

R⁸ is H or -CH₃;

CY is Ci-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, or substituted or

unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, Br, I, -OH, -CN, Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci- C₄fluoroalkoxy, or Ci-C₄alkoxy;

or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof.

[00152] In some embodiments, CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, -CN, -CH₃, -CF₃, -

OH, -OCF₃, or -OCH₃. In some embodiments,

1 , or 2. In some embodiments, n is 0 or 1. In some embodiments, CY is cyclopropyl, cyclobutyl, cyclopentyl, cyclopent- 1 -enyl, 2-chlorocyclopent-l-enyl, cyclohexyl, cyclohex-l-enyl, 2-chlorocyclohex-l-enyl, phenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6- difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4- dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-triiluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3 -methylphenyl, 4- methylphenyl, 2-cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. In some embodiments, CY is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, or 2-methylphenyl. In some embodiments, CY is phenyl, 2-fluorophenyl, or 2-chlorophenyl. In some embodiments, CY is phenyl.

[00153] In some embodiments, the compound of Formula (I) has the following structure:

[00154] In some embodiments the LPA receptor antagonist has the structure of Formula (II):

Formula (II).

[00155] In some embodiments, R¹ is -CO₂H. In some embodiments, L¹ is -CH₂-, -CH₂CH₂-, - CH₂CH₂CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH(CH₂CH₃)-, -C(CH₂CH₃)₂-, -CH₂CH(CH₃)-, - CH C(CH₃)₂-, cyclopropyl- 1 , 1 -diyl, cyclopropyl- 1 ,2-diyl, cyclobutyl- 1 , 1 -diyl, cyclopentyl- 1 , 1 -diyl or cyclohexyl- 1,1 -diyl. In some embodiments, L¹ is -CH₂-, -C(CH₃)₂-, or -C(CH₂CH₃)₂-. In some embodiments, L¹ is -CH₂- or cyclopropyl- 1,1 -diyl. In some embodiments, L¹ is -CH₂-. In some embodiments, L¹ is cyclopropyl- 1 , 1 -diyl, cyclobutyl- 1,1 -diyl, cyclopentyl- 1 , 1 -diyl or cyclohexyl- 1,1-diyl. In some embodiments, L¹ is cyclopropyl- 1,1 -diyl. In some embodiments, R³ is H. In some embodiments, R³ is -CH₃. In some embodiments, each of R^c is independently selected from F, CI, - CH₃, and -CF₃; n is 0 or 1.

[00156] In some embodiments, the LPA1 receptor antagonist is:

[00157] (R)-2-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A):

[00158] (R)-l-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4- yl)cyclopropanecarboxylic acid

[00159] (R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl-4- yl)acetic acid (Compound C):

[00160] {5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4 yl}-carbamic acid (R)-l-phenyl-

[00161] 1 -(4'- (4-[(R)- 1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl} -biphenyl- 4-yl)-cyclopropanecarboxylic

[00162] l- {4'-[4-((R)-l-Phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}- cyclopropanecarboxylic acid (Compound F):

[00163] (3-Methyl-5- {4'-[ l -(5-oxo-2,5-dihydro-[ l ,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl} isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound G): or

[00164] (3-Methyl-5- {4'-[ 1 -(lH-tetrazol-5-yl)-cyclopropyl]-biphenyl-4-yl} -isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound Η):

[00165] In some embodiment the LPA1 receptor antagonist has structure of Formula (III):

wherein

R¹ is -C0₂H, -C0₂R^D, tetrazolyl, 5-oxo-2,5-dihydro-[ l ,2,4]oxadiazol-3-yl, -

C(=0)NHS0₂CH₃, or -C(=0)NHS0₂CH₂CH₃; R^D is -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, CH(CH₃)₂, -CH₂CH₂CH₂CH₃, or -C(CH₃)₃;

L¹ is absent, or a Ci-Cgalkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃; R⁴ is -NHC(=0)OCH(R⁸)-CY;

R⁸ is H, or -CH₃;

CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is

substituted with 1 or 2 R^c; each R^c is independently F, CI, Br, I, -OH, -CN, C C4alkyl, Ci-C4fiuoroalkyl, Ci-C4fluoroalkoxy, or Ci-C4alkoxy;

or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically

acceptable solvate thereof.

[00166] In some embodiments, R¹ is -CO₂H or -C0₂R^D. In some embodiments, R¹ is -CO₂H. In some embodiments, L¹ is -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH₂CH₂-, -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, -CH₂CH₂CH₂-, or -CH₂CH₂CH₂CH₂-. In some embodiments, L¹ is -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, or -CH₂CH₂CH₂CH₂-. In some embodiments, L¹ is -CH₂CH₂CH₂-, or -CH₂CH₂CH₂CH₂-. In some embodiments, R³ is H. In some embodiments, R³ is -CH₃. In some embodiments, R⁸ is -CH₃. In some embodiments, each of R^c is independently selected from F, CI, -CH₃, and -CF₃.

[00167] In some embodiments, R⁴ is

[00168] In some embodiments, CY is a substituted or unsubstituted phenyl, wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, -CN, -CH₃, -CF₃, -

OH, -OCF₃, or -OCH₃.

[00169] In some embodiments, the LPAl antagonist is selected from: 6-(4- {4-[l-(2-Chloro-phenyl)- ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hex-5-)moic acid, 7-(4-{4-[l-(2-chloro- phenyl)-ethoxycarbonylamino] -3 -methyl -isoxazol-5-yl}-phenyl)-hept-6-ynoic acid, or a

pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof

[00170] In some embodiments, the LPAl receptor antagonist has the structure of Formula (IV):

wherein:

A is an aryl or heteroaryl ring;

R³ is H, Ci-C₄alkyl, CrC₄fluoroalkyl;

R⁴ is -NHC(=0)OCH(R⁸)-CY, or -NHC(=0)0-CY;

R⁸ is H, C C₄alkyl, C_rC₄fluoroalkyl;

CY is a substituted or unsubstituted C₃-Cscycloalkyl, a substituted or unsubstituted

phenyl, or a substituted or unsubstituted monocyclic heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently selected from F, CI, Br, I, -CN, -OH, C C₄alkyl, C_rC₄fluoroalkyl, Ci-C₄fluoroalkoxy, C

C₄alkoxy, and Ci-C₄heteroalkyl;

R⁵ and R⁶ are each independently selected from H, halogen, -CN, -N0₂, -OH, -OR¹⁰, C

C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl; R¹⁰ is selected from Ci-Ceaikyl, Ci-Ceheteroalkyl, Ci-Cefluoroalkyl, a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl; or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof.

[00171] In some embodiments, A is phenyl, or a 5- or 6-membered monocyclic heteroaryl. In some embodiments, A is a phenyl, pyridinyl, thiazolyl, or pyrimidinyl. In some embodiments, R⁵ and R⁶ are each independently selected from hydrogen, halogen, or hydroxy. In some embodiments, R³ is methyl, ethyl, isopropyl or trifluoromethyl. In some embodiments, R³ is methyl. In some embodiments, CY is a substituted or unsubstituted CYcycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or

[00172] In some embodiments, the LPA1 antagonist has one of the following structures:

[00173] In some embodiments, the LPA1 receptor antagonist has the structure of Formula (V):

wherein:

A is an aryl or heteroaryl ring;

B is an aryl or heteroaryl ring; L is absent, C_rC₄alkylene, C_rC₄heteroalkylene, -0-, -S-, -SO-, -S0₂-, -NH-, -NR²-, or -

C(=0)-; R² is Ci-C₄alkyl;

R³ is H, C C₄alkyl, or C C₄fluoroalkyl;

R⁴ is -NHC(=0)OCH(R⁸)-CY, or -NHC(=0)0-CY;

R⁸ is H, Ci-C₄alkyl, or Ci-C₄fluoroalkyl;

CY is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently selected from F, CI, Br, I, -CN, -OH, C C₄alkyl, C_r

C₄fluoroalkyl, Ci-C₄fiuoroalkoxy, C C₄alkoxy, and C C₄heteroalkyl;

R⁵ and R⁶ are each independently selected from H, halogen, -CN, -N0₂, -OH, ^ n lO r

Λ-

Qalkyl, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, CrC₄alkoxy, and Ci-C₄heteroalkyl;

R^5a and R^6a are each independently selected from H, halogen, -CN, -N0₂, -OH, -OR¹⁰, -

S(=0)2R¹⁰, substituted or unsubstituted Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl or substituted or unsubstituted Ci-C₆heterocycloalkyl;

R¹⁰ is selected from Ci-Cgalkyl, Ci-Ceheteroalkyl, Ci-Cefluoroalkyl, a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

acceptable solvate thereof.

[00174] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the

[00175] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the

groups

and R^6aare in a 1 ,4-relationship on ring A (i.e. an para relationship).

[00176] In some embodiments, A is a phenyl ring. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, A is a 6-membered monocyclic heteroaryl. In some

embodiments, A is a pyridinyl ring. In some embodiments, L is absent. In some embodiments, L is absent and A-L-B is bi-aromatic. In some embodiments, L is absent and A-L-B is biphenyl. In some embodiments, B is a phenyl ring. In some embodiments, B is a monocyclic heteroaryl. In some embodiments, B is a 6-membered monocyclic heteroaryl. In some embodiments, B is a pyridinyl ring. In some embodiments, A-L-B is phenyl-pyridyl. In some embodiments, R⁵ and R⁶ are each independently selected from hydrogen, halogen, or hydroxy. In some embodiments, R^5a and R⁶ are each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl or substituted or unsubstituted heterocycloalkyl. In some embodiments, R³ is methyl, ethyl, isopropyl or trifluoromethyl.

[00177] In some embodiments, L is absent, -CH₂-, -CH₂0-, -OCH₂-, -CH₂S-, -SCH₂-, -CH₂NH-, - NHCH₂-, -0-, -S-, or -NH-. In some embodiments, L² is absent.

[00178] In some embodiments, the LPA1 antagonist has a structure selected from:

/ " ; or a pharmaceutically acceptable salt, prodrug, active metabolite, pharmaceutically acceptable solvate thereof. [00179] In some embodiments, the LPA receptor antagonist has the structure of Formula (VI) or a pharmaceutically acceptable salt thereof:

Formula (VI)

wherein,

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, or tetrazolyl;

R^D is H or Ci-C₆alkyl;

R^E is Ci-Cealkyl, C3-Cecycloalkyl, or substituted or unsubstituted phenyl;

L³ is a substituted or unsubstituted C3-C₆alkylene, a substituted or unsubstituted C₃-

C₆fluoroalkylene, or a substituted or unsubstituted C3-C₆heteroalkylene, where if L³ is substituted then L³ is substituted with 1, 2 or 3 R¹³; each R¹³ is independently F, Ci- C₄alkyl, Ci-C₄fluoroalkyl, or -OH;

each R^c is independently halogen, -CN, -N0₂, -OH, Ci-C₄alkyl, Ci-C₄fluoroalkyl, C_r

C₄fluoroalkoxy, Ci-C₄alkoxy, or CrC₄heteroalkyl;

R³ is H or Ci-C₄alkyl;

n is 0, 1, or 2.

[00180] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, R¹ is -C0₂R^D or -C(=0)NHS0₂R^E. In some embodiments, R¹ is -C0₂R^D. In some embodiments, R¹ is -C0₂H. In some embodiments, R¹ is -C(=0)NHS0₂R^E In some embodiments, R^E is Ci-C₆alkyl. In some embodiments, R^E is -CH₃ or - CH₂CH₃. In some embodiments, R^E is -CH₃. In some embodiments, R^D is H, -CH₃ or -CH₂CH₃. In some embodiments, R^D is -CH₂CH₃. In some embodiments, R^D is H.

[00181] In some embodiments, each R^c is independently halogen, -CN, -OH, -CH₃, -CH₂CH₃, - CH(CH₃)₂, -CF₃, -OCF₃, -OCH₃ or -OCH₂CH₃. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[00182] In some embodiments,

is phenyl, 2-fluorophenyl, 2,3 -difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. In some is phenyl, 2 , 2-chlorophenyl, 2-trifluoromethylphenyl, or , is phenyl, 2-fluorophenyl, or 2-chlorophenyl.

In some em o ments, s phenyl.

[00183] In some embodiments, R³ is -H, -CH₃ or -CH₂CH₃. In some embodiments, R³ is -CH₃ or - CH₂CH₃. In some embodiments, R³ is -CH₃.

[00184] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; R^D is H or C C₄alkyl; R^E is C C₄alkyl; R³ is -H, -CH₃ or -CH₂CH₃.

[00185] In some embodiments, L³ is a substituted or unsubstituted C₃-C₄alkylene, a substituted or unsubstituted C₃-C₄fluoroalkylene, or a substituted or unsubstituted C₃-Ceheteroalkylene; where if L³ is substituted then L³ is substituted with 1 , 2 or 3 R¹³; each R¹³ is independently F, -CH₃, -CH₂CH₃, - CF₃, or -OH.

[00186] In some embodiments, L³ is a substituted or unsubstituted butylene, a substituted or unsubstituted fluorobutylene, or a substituted or unsubstituted difluorobutylene; where if L³ is substituted then L³ is substituted with 1 or 2 R¹³.

[00187] In some embodiments, L³ is a substituted or unsubstituted C₃-Ceheteroalkylene; where if L³ is substituted then L³ is substituted with 1 or 2 R¹³.

[00188] In some embodiments, L³ is -(substituted or unsubstituted C₃-C₄alkylene)-0-, -(substituted or unsubstituted Ci-C₃alkylene)-0-(substituted or unsubstituted Ci-C₃alkylene)-, -0-(substituted or unsubstituted C₃-C₄alkylene)-, -(substituted or unsubstituted C₃-C₄alkylene)-S-, -(substituted or unsubstituted Ci-C₃alkylene)-S-(substituted or unsubstituted Ci-C₃alkylene)-, -S-(substituted or unsubstituted C₃-C₄alkylene)-, -(substituted or unsubstituted C₃-C₄alkylene)-NH-, -(substituted or unsubstituted Ci-C₃alkylene)-NH-(substituted or unsubstituted Ci-C₃alkylene)-, or -NH-(substituted or unsubstituted C₃-C₄alkylene)-.

[00189] In some embodiments, L³ is -NH-(substituted or unsubstituted C₃-C₄alkylene); where if L³ is substituted then L³ is substituted with R¹³.

[00190] In some embodiments, L³ is -(substituted or unsubstituted Ci-C₃alkylene)-0-(substituted or unsubstituted Ci-C₃alkylene)-, or -(substituted or unsubstituted Ci-C₃alkylene)-S-(substituted or unsubstituted Ci-C₃alkylene)-; where if L³ is substituted then L³ is substituted with R¹³.

[00191] In some embodiments, L³ is -(substituted or unsubstituted ethylene)-0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-(substituted or unsubstituted methylene)-; where if L³ is substituted then L³ is substituted with R¹³. [00192] In some embodiments, L³ is a substituted or unsubstituted C₃-C₄alkylene, a substituted or unsubstituted C3-C₄fluoroalkylene, or a substituted or unsubstituted C3-C₆heteroalkylene.

[00193] In some embodiments, L³ is a substituted or unsubstituted butylene, a substituted or unsubstituted fluorobutylene, or a substituted or unsubstituted difluorobutylene.

[00194] In some embodiments, L³ is a substituted or unsubstituted C3-C6heteroalkylene. In some embodiments, L³ is a substituted or unsubstituted C3-C₄heteroalkylene.

[00195] In some embodiments, L³ is -NH-(substituted or unsubstituted C₃-C₄alkylene).

[00196] In some embodiments, L³ is -(substituted or unsubstituted Ci-C₃alkylene)-0-(substituted or unsubstituted Ci-C₃alkylene)-, or -(substituted or unsubstituted Ci-C₃alkylene)-S-(substituted or unsubstituted Ci-C₃alkylene)-. In some embodiments, L³ is -(substituted or unsubstituted ethylene)-

0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-

(substituted or unsubstituted methylene)-.

[00197] In some embodiments, L³ is substituted with 1 , 2 or 3 R¹³. In some embodiments, L³ is substituted with 1 or 2 R¹³. In some embodiments, L³ is substituted with R¹³. In some embodiments, L³ is unsubstituted. In some embodiments, if L³ is substituted then L³ is substituted with 1 , 2 or 3 R¹³. In some embodiments, if L³ is substituted then L³ is substituted with 1 or 2 R¹³. In some embodiments, if L³ is substituted then L³ is substituted with R¹³. In some embodiments, L³ is unsubstituted. In some embodiments, each R¹³ is independently F, Ci-C₄alkyl, Ci-C₄fluoroalkyl, or - OH. In some embodiments, each R¹³ is independently F, Ci-C₄alkyl, or -OH. In some embodiments, each R¹³ is independently Ci-C₄alkyl, or -OH. In some embodiments, each R¹³ is independently F, - CH₃, -CH₂CH₃, -CF₃, or -OH. In some embodiments, each R¹³ is independently F, -CH₃, or -OH. In some embodiments, each R¹³ is independently -CH₃, or -OH. In some embodiments, R¹³ is F, -CH₃, -CH₂CH₃, -CF₃, or -OH. In some embodiments, R¹³ is F, -CH₃, -CH₂CH₃, or -OH. In some embodiments, R¹³ is -CH₃ or -OH. In some embodiments, R¹³ is C C₄alkyl, or -OH.

[00198] In some embodiments, the LPA receptor antagonist has the structure of Formula (VII) or a pharmaceutically acceptable salt thereof:

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, -CN, or tetrazolyl;

R^D is H or C C₆ alkyl; ^E is Ci-C₆ alkyl or a substituted or unsubstituted phenyl;

L² is absent, -C(=0)-, -N(R^D)-, substituted or unsubstituted C₁-C4 alkylene, or substituted or unsubstituted C₁-C4 heteroalkylene, where if L² is substituted, then L² is substituted with R¹², where R¹² is F, C C₄alkyl, -OH, or -OR^D;

ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic

Ci-Csheteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴, each R¹⁴ is independently selected from halogen, -CN, -OH, Ci-C₄alkyl, C C₄fluoroalkyl, Ci-C₄fiuoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl;

L⁴ is absent, or a substituted or unsubstituted C C₄ alkylene, where if L⁴ is substituted then L⁴ is substituted with R¹³, where R¹³ is F, C C₄alkyl, -OH, or -OR^D;

R³ is H or Ci-C₄ alkyl;

each R^c is independently selected from halogen, -CN, -OH, Ci-C₄alkyl, Ci-C₄fluoroalkyl,

Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl;

n is 0, 1 or 2.

[00199] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, R¹ is -C0₂R^D or -C(=0)NHS0₂R^E. In some embodiments, R¹ is -C0₂R^D. In some embodiments, R¹ is -CO₂H. In some embodiments, R¹ is -C(=0)NHS0₂R^E In some embodiments, R^E is C₁-C6 alkyl. In some embodiments, R^E is -C¾ or - CH2CH3. In some embodiments, R^D is H, -CH3 or -CH₂CH3. In some embodiments, R^D is H.

[00200] In some embodiments, R³ is Ci-C₄alkyl. In some embodiments, R³ is H, -CH₃, or -CH₂CH₃. In some embodiments, R³ is -CH₃, or -CH₂CH₃. In some embodiments, R³ is -CH₃. In some embodiments, R³ is H.

[00201] In some embodiments, L² is absent, -C(=0)-, -N(R^D)-, substituted or unsubstituted C₁-C₄ alkylene, or substituted or unsubstituted C₁-C₄ heteroalkylene, where if L² is substituted, then L² is substituted with R¹². In some embodiments, L² is -N(R^D)-, substituted or unsubstituted C1-C2 alkylene, or substituted or unsubstituted C₁-C₂ heteroalkylene, where if L² is substituted, then L² is substituted with R¹². In some embodiments, L² is -N(H)-, -N(CH₃)-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L² is substituted, then L² is substituted with R¹². In some embodiments, L² is -N(H)-. In some embodiments, L² is substituted or unsubstituted methylene, where if L² is substituted, then L² is substituted with R¹².

[00202] In some embodiments, L² is selected from a bond, CrC₄alkylene, -C(=0)-, -CH(OH)-, - CH(OR^D)-, -CH₂CH(OH)-, - CH₂CH(OR^D)-, -CH₂S-, -CH₂S(0)-, -CH₂S(0)₂-, -SCH₂-, - S(0)CH₂-, - S(0)₂CH₂-, -CH₂O-, -OCH₂-, -S(0)₂CH₂-, -N(H)-, -CH₂N(H)-, or -N(H)CH₂-.

[00203] In some embodiments, L² is absent, -C(=0)-, -NH-, -N(CH₃)-, -CH₂-, -CH₂CH₂-, -CH(CH₃)-, -CH₂CH(CH₃)-, -CH(CH₃)CH₂-, -CH(OH)-, -CH(OR^D)-, -CH₂CH(OH , -CH₂CH(OR^D)-, -

CH(OH)CH₂-, -CH(OR^D)CH₂-, -CH₂NH-, -CH(CH₃)NH-, -NHCH₂- or -NHCH(CH₃)-. In some embodiments, L² is -NH-, -N(CH₃)-, -CH₂-, -CH(CH₃)-, -CH(OH)-, -CH(O ^D)-, -CH₂NH-, - CH(CH₃)NH-, -NHCH₂- or -NHCH(CH₃)-. In some embodiments, L² is -NH-, -N(CH₃)-, -CH₂NH-, -CH(CH₃)NH-, -NHCH₂- or -NHCH(CH₃)-. In some embodiments, L² is -NH-. In some

embodiments, L² is -CH₂-, -CH(CH₃)-, -CH(OH)-, -CH(OR^D)-, -CH₂NH-, -CH(CH₃)NH-, -NHCH₂- or -NHCH(CH₃)-. In some embodiments, L² is -CH₂-, -CH(CH₃)-, -CH(OH)-, or -CH(OR^D)-. In some embodiments, L² is -CH₂- or -CH(OH)-. In some embodiments, L² is -CH(OH)-. In some embodiments, L² is -CH₂-.

[00204] In some embodiments, R¹² is F, -CH₃, -CH₂CH₃, -OH, -OCH₃, or -OCH₂CH₃. In some embodiments, R¹² is -CH₃, or -OH.

[00205] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; L² is absent, -C(=0)-, -NH-, - N(CH₃)-, -CH₂-, -CH₂CH₂-, -CH(CH₃)-, -CH₂CH(CH₃)-, -CH(CH₃)CH₂-, -CH(OH)-, -CH(OR^D)-, - CH₂CH(OH)-, -CH₂CH(OR^D)-, -CH(OH)CH₂-, -CH(OR^D)CH₂-, -CH₂NH-, -CH(C¾)NH-, - NHCH₂- or -NHCH(CH₃)-; L⁴ is absent, -CH₂-, -CH(CH₃)-, -CH(OH)-, -CH₂CH₂-, -CH₂CH(CH₃)-, - CH(CH₃)CH₂-, -CH₂CH(OH)-, or -CH(OH)CH₂-; R³ is -H, -CH₃ or -CH₂CH₃.

[00206] In some embodiments, each R^c is halogen, -OH, -CH₃, -CH₂CH₃, -CF₃, -OCF₃, -OCH₃, - OCH₂CH₃, -CH₂OCH₃, -CH₂OCH₂CH₃, or -CH₂N( CH₃)₂. In some embodiments, each R^c is independently selected from halogen, -OH, -CH₃, -CH₂CH₃, -CF₃, -OCF₃, -OCH₃ and -OCH₂CH₃.

[00207] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00208] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00209] In some embodiments, ring A is a substituted or unsubstituted monocyclic C

Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00210] In some embodiments, ring A is a substituted or unsubstituted 5-membered monocyclic C_r C^eteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00211] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C₃- Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00212] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L²- and -L⁴- are in a 1 ,2-relationship on ring A (i.e. an ortho relationship). In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L²- and - L⁴- are in a 1 ,3 -relationship on ring A (i.e. a meta relationship). In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L²- and -L⁴- are in a 1 ,4- relationship on ring A (i.e. a para relationship).

[00213] In some embodiments, ring A is unsubstituted or monosubstituted with R¹⁴. In some embodiments, ring A is unsubstituted. In some embodiments, ring A is monosubstituted with R¹⁴.

[00214] In some embodiments, L⁴ is absent, or a substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L⁴ is substituted, then L⁴ is substituted with R¹³. In some embodiments, L⁴ is absent. In some embodiments, L⁴ is a substituted or unsubstituted methylene, where if L⁴ is substituted, then L⁴ is substituted with R¹³. In some embodiments, L⁴ is a substituted or unsubstituted ethylene, where if L⁴ is substituted, then L⁴ is substituted with R¹³.

[00215] In some embodiments, R¹³ is F, -CH₃, -CH₂CH₃, -OH, -OCH₃, or -OCH₂CH₃. In some embodiments, R¹³ is -CH₃.

[00216] In some embodiments, L⁴ is absent, -CH₂-, or -CH(CH₃)-.

[00217] In some embodiments, L² is -NH-, -CH₂-, -CH₂CH₂-, -CH(CH₃>, -CH₂CH(CH₃)-, - CH(CH₃)CH₂-, -CH(OH)-, -CH₂CH(OH)-, -CH(OH)CH₂-, -CH₂NH-, -CH(CH₃)NH-, -NHCH₂- or - NHCH(CH₃)-; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1 -4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴; L⁴ is absent, -CH₂-, or -CH(CH₃)-; R³ is -CH₃.

[00218] In some embodiments, ring A is a substituted or unsubstituted phenyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00219] In some embodiments, ring A is a substituted or unsubstituted monocyclic C

[00220] In some embodiments, ring A is a substituted or unsubstituted 5-membered monocyclic C _r C4heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00221] In some embodiments, ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00222] In some embodiments, each R¹⁴ is independently selected from halogen, -CN, -OH, -CH₃, - CH₂CH₃, -CF₃, -OCF₃, -OCH₃ and -OCH₂CH₃. In some embodiments, each R¹⁴ is halogen, -CN, - OH, -CH₃, -CH₂CH₃, -CF₃, -OCF₃, -OCH₃ or -OCH₂CH₃. In some embodiments, each R¹⁴ is independently selected from halogen, -OH, and -CH₃. . In some embodiments, is halogen, -OH or -C¾. In some embodiments, each R is independently selected from halogen and -C¾.

[00224] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C3- Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00225] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, a substituted or unsubstituted pyridazinylene, a substituted or unsubstituted pyrimidinylene, a substituted or unsubstituted pyrazinylene, or a substituted or unsubstituted triazinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴.

[00226] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, where if ring A

[00228] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; R^D is H or d-C₄ alkyl; R^E is C_r C₄ alkyl; L² is -CH₂-, -CH(CH₃)-, or -CH(OH)-; ring A is a substituted or unsubstituted 5-membered monocyclic Ci-C₄heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with R¹⁴; L⁴ is -CH₂- or -CH(CH₃)-; p is 0 or 1.

[00229] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; R^D is H or C1-C4 alkyl; R^E is d- C₄ alkyl; L² is -CH₂-, -CH(CH₃)-, or -CH(OH)-; ring A is a substituted or unsubstituted 5-membered monocyclic Ci-C heteroarylene containing 1-4 N atoms and 0 or 1 O atoms, where if ring A is substituted, then ring A is substituted with R¹⁴, R¹⁴ is halogen, -CN, -OH, -CH₃, -CH₂CH₃, -CF₃, - OCF₃, -OCH₃ or -OCH₂CH₃; L⁴ is -CH₂- or -CH(CH₃)-; n is 0 or 1.

[00230] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; R^D is H or C C₄alkyl; R^E is C Qalkyl; L² is -NH-, -CH₂-, -CH(CH₃)-, -CH(OH)-, -NHCH₂- or -NHCH(CH₃)-; ring A is a substituted or unsubstituted 6-membered monocyclic C₃-C₅heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with R¹⁴; L⁴ is absent, -CH₂-, or -CH(CH₃)-; p is 0 or 1.

[00231] In some embodiments, R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E; R^D is H or C C₄alkyl; R^E is C Qalkyl; L² is -NH-, -CH₂-, -CH(CH₃)-, -CH(OH)-, -NHCH₂- or -NHCH(CH₃)-; ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with R¹⁴, R¹⁴ is halogen, -CN, -OH, -CH₃, -CH₂CH₃, -CF₃, -OCF₃, -OCH₃ or -OCH₂CH₃; L⁴ is absent, -CH₂-, or -CH(CH₃)-; n is 0 or 1.

[00232] In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some

embodiments, n is 0. In some embodiments, n is 1.

[00233] In some embodiments, (^R )n is phenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3- trifiuoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. [00234] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[00235] In some embodiments, the LPA1 receptor antagonist is selected from compounds (or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof) described in U.S. Patent Nos. 6,964,975; 7,288,558 and U.S. Application

Publication No. 2006/0194850, each of which is herein incorporated by reference.

[00236] In some embodiments, the LPA1 receptor antagonist is is 3-[[[4-[4-[[[l-(2- chlorophenyl)ethoxy]carbonyl]amino]-3-methyl-5-isoxazolyl]phenyl]methyl]thio]-propanoic acid, or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof.

[00237] In some embodiments, the LPA1 receptor antagonists contemplated for use herein (including pharmaceutically acceptable salts, solvates, and prodrugs thereof) are antagonists of LPA 1 and optionally at least one of the LPA receptors selected from LPA₂, LPA₃, LPA_4; LPA₅ and LPA₆. In one embodiment, the LPA receptor antagonists are antagonists LPAi and/or LPA₃. In some embodiments, the LPA compounds are antagonists of LPAi and/or LPA₂.

[00238] In one aspect, LPAI receptor antagonists contemplated for use in any of the embodiments disclosed herein are selective LPAI receptor antagonists. "Selectivity" for one LPA receptor versus other LPA receptors means that the compound has an IC50 (Ca Flux assay) for the indicated LPA receptor that is at least 10-fold less than the IC₅₀ for other LPA receptors. In some embodiments, selectivity for one LPA receptor versus other LPA receptor means that the compound has an IC₅₀ for the indicated LPA receptor that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC₅₀ for other LPA receptors. For example, a selective LPAi receptor antagonist has an IC₅₀ that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC₅₀ for other LPA receptors (e.g. LPA₂, LPA₃).

[00239] In some embodiments, pharmaceutically acceptable salts are obtained by reacting an LPA receptor antagonist compound with acids. Pharmaceutically acceptable salts are also obtained by reacting an LPA receptor antagonist compound with a base. In one aspect LPA receptor antagonists described herein are used as pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid to form a salt such as, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid salt, a metaphosphoric acid salt, and the like; or with an organic acid to form a salt, such as, for example, an acetic acid salt, a propionic acid salt, a hexanoic acid salt, a cyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid salt, a malonic acid salt, a succinic acid salt, a malic acid salt, a maleic acid salt, a fumaric acid salt, a trifluoroacetic acid salt, a tartaric acid salt, a citric acid salt, a benzoic acid salt, a 3-(4-hydroxybenzoyl)benzoic acid salt, a cinnamic acid salt, a mandelic acid salt, a methanesulfonic acid salt, an ethanesulfonic acid salt, a 1 ,2-ethanedisulfonic acid salt, a 2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, a toluenesulfonic acid salt, a 2-naphthalenesulfonic acid salt, a 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid salt, a glucoheptonic acid salt, a 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid) salt, a 3- phenylpropionic acid salt, a trimethylacetic acid salt, a tertiary butylacetic acid salt, a lauryl sulfuric acid salt, a gluconic acid salt, a glutamic acid salt, a hydroxynaphthoic acid salt, a salicylic acid salt, a stearic acid salt, a muconic acid salt, a butyric acid salt, a phenylacetic acid salt, a phenylbutyric acid salt, a valproic acid salt, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. a lithium salt, a sodium salt, potassium salt), an alkaline earth ion (e.g. a magnesium salt, or a calcium salt), or an aluminum ion (e.g. an aluminum salt). In some cases, LPA receptor antagonist compounds described herein are reacted with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a tri ethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, a tris(hydroxymethyl)methylamine salt. In other cases, LPA receptor antagonist compounds described herein form salts with amino acids such as, but not limited to, an arginine salt, a lysine salt, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, LPA receptor antagonist compounds are prepared and utilized as a sodium salt.

[00240] In some embodiments, the LPA receptor antagonist compounds described herein possess one or more stereocenters and each center exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.

[00241] In some embodiments, LPA antagonists presented herein are used as a single enantiomer. In some embodiments, LPA antagonists presented herein are used as a single enantiomer that is optically pure (i.e. substantially free of the other isomer). In some embodiments, LPA antagonists presented herein are used as a single enantiomer of any optical purity. In some embodiments, LPA antagonists presented herein are used as a racemic mixture.

[00242] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

[00243] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.

[00244] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structures presented herein, as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.

Antibodies

[00245] In some embodiments, the LPA1 receptor antagonist is an antibody specific for the LPA1 receptor. A non-limiting example of a LPA1 antibody is Gene ID 1902, Synthetic peptide:

CQ SENPTGPTEGSDRS, corresponding to C-term amino acids 328-344 of human EDG2; human lysophosphatidic acid 1 (LPAi) amino acids 342-359 (DRSASSLNHTILAGVHSN) (see Catalog no. 10005280 of Cayman Chemical).

[00246] Fragments of antibodies are also contemplated. In one aspect, the LPAI antagonist is an antigen binding fragment of a LPAI antibody (e.g. Fab, F(ab¾, Fv, scFv, single binding chain polypeptide).

[00247] In one aspect, the antibody is a polyclonal, monoclonal or chimeric antibody or a fragment thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of animals immunized with an antigen. A monoclonal antibody (MAb) contains a substantially homogeneous population of antibodies specific to antigens, which population contains substantially similar epitope binding sites. MAbs are obtained by methods known to those skilled in the art. See, for example Kohler and Milstein, Nature 256:495-497 (1975); U.S. Pat. No. 4,376,110; Ausubel et ah, eds., Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1987, 1992); and Harlow and Lane ANTIBODIES: A Laboratory Manual Cold Spring Harbor Laboratory (1988); Colligan et ah, eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), the contents of which references are incorporated herein by reference for such disclosures.

[00248] Chimeric antibodies are molecules wherein different portions of the molecules are derived from different animal species. Chimeric antibodies and methods for their production are known. Peptides

[00249] In some embodiments, the LPAI receptor antagonist is a peptide that can bind to LPAI receptor. In other embodiments, the LPAI receptor antagonist is a peptidoimimetic analog of a peptide ligand. Peptide ligands include, but are not limited to, members of random peptide libraries; (see, e.g., Lam et ah, 1991 , Nature 354:82-84; Houghten et ah, 1991 , Nature 354:84-86), and combinatorial chemistry-derived molecular libraries made of D- and/or L- configuration amino acids, phosphopeptides (including, but not limited to, members of random or partially degenerate, directed phosphopeptide libraries; see, e.g., Songyang et ah, 1993, Cell 72:767-778), recombinant (e.g., phage display libraries), and in vitro translation-based libraries.

[00250] In some embodiments, the LPAl antagonist is a LPAl blocking pepetide. A non-limiting example of a LPAl blocking pepetide is peptide sequence: human lysophosphatidic acid ceceptor 1 (LPAi) amino acids 342-359 (see Catalog no. 10006894 of Cayman Chemical).

Peptidomimetic

[00251] In some embodiments, the LPAl receptor antagonist is a peptidomimetic. Peptidomimetic ligands include compounds from a benzodiazepine library (see e.g., Bunin et ah, 1994, Proc. Natl. Acad. Sci. USA 91 :4708-4712) that can be adapted for use for the methods disclosed herein, peptoid libraries disclosed in, e.g., Simon et ah, 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371 and peptidomimetics in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library (Ostresh et al. 1994, Proc. Natl. Acad. Sci. USA 91 : 11138-1 1142).

Oligonucleotide or an Aptamer

[00252] In further embodiments, the LPAl receptor antagonist is an oligonucleotide or an aptamer. In some other embodiments, the LPAl antagonist is a nucleic acid.

[00253] In some embodiments, the LPAl antagonist is a nucleic acid comprising a sequence at least partially complementary with the LPAl receptor DNA coding region. In some embodiments, the nucleic acid comprises an antisense sequence.

Certain Terminology

[00254] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[00255] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may be a saturated alkyl group or an unsaturated alkyl group. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like. In one aspect the alkyl is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[00256] The term "alkyl ene" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. Typical alkylene groups include, but are not limited to, -CH₂-, -CH(CH₃)-, -C(CH3)₂-, - CH₂CH₂-, -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and the like.

[00257] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[00258] "Aryl" refers to phenyl or naphthalenyl. In one aspect, an aryl is a phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Examplary arylenes include, but are not limited to, phenyl- 1 ,2-ene, phenyl- 1,3-ene, and phenyl- 1,4-ene.

[00259] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., an cycloalkylene group, such as, but not limited to, cyclopropan-l ,l-diyl, cyclobutan-l ,l-diyl, cyclopentan- 1 , 1 -diyl, cyclohexan-l,l-diyl, cyclohexan-l ,4-diyl, cycloheptan- 1 , 1 -diyl, and the like).

[00260] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo or iodo.

[00261] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halide atoms.

[00262] The term "haloalkylene" refers to an alkylene group in which one or more hydrogen atoms are replaced by one or more halide atoms.

[00263] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.

[00264] The term "fiuoroalkylene" refers to an alkylene in which one or more hydrogen atoms are replaced by a fluorine atom.

[00265] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, or combinations thereof.

[00266] The term "heteroalkylene" refers to an alkylene group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, or combinations thereof. Examplary heteroalkylenes include, but are not limited to, -OCH₂-, - OCH(CH₃)-, -OC(CH₃)₂-, -OCH₂CH₂-, -CH₂0-, -CH(CH₃)0-, -C(CH₃)₂0-, -CH₂CH₂0-, - CH₂OCH₂-, -CH₂OCH₂CH₂-, -CH₂CH₂OCH₂-, -SCH₂-, -SCH(CH₃)-, -SC(CH₃)₂-, -SCH₂CH₂-, - CH₂S-, -CH(CH₃)S-, -C(CH₃)₂S-, -CH₂CH₂S-, -CH₂SCH₂-, -CH₂SCH₂CH₂-, -CH₂CH₂SCH₂-, -

S0₂CH₂-, -S0₂CH(CH₃)-, -S0₂C(CH₃)₂-, -S0₂CH₂CH₂-, -CH₂S0₂-, -CH(CH₃)S0₂-, -C(CH₃)₂S0₂-, -CH₂CH₂S0₂-, -CH₂S0₂CH₂-, -CH₂S0₂CH₂CH₂-, -CH₂CH₂S0₂CH₂-, -NHCH₂-, -NHCH(CH₃)-, - NHC(CH₃)₂-, -NHCH₂CH₂-, -CH₂NH-, -CH(CH₃) H-, -C(CH₃)₂NH-, -CH₂CH₂NH-, - CH₂CH₂CH₂NH-, -NHCH₂CH₂CH₂-, -CH₂NHCH₂-, -CH₂NHCH₂CH₂-, -CH₂CH₂NHCH₂-, and the like.

[00267] The term "heteroaryl" refers to an aromatic ring that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. In one aspect, a heteroaryl contains 0-3 N atoms. In another aspect, a heteroaryl contains 1-3 N atoms. In another aspect, a heteroaryl contains 0-3 N atoms, 0-1 O atoms, and 0-1 S atoms. In another aspect, a heteroaryl is a monocyclic or bicyclic heteroaryl. In one aspect, heteroaryl is a Ci-Cgheteroaryl. In one aspect, monocyclic heteroaryl is a Ci-Csheteroaryl. In one aspect, monocyclic heteroaryl is a 5- membered or 6-membered heteroaryl. In one aspect, bicyclic heteroaryl is a C₆-C₉heteroaryl.

Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroaryl ene group).

[00268] A "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicychc also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C₂-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In one aspect, a heterocycloalkyl contains 0-2 N atoms. In another aspect, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms or 0-1 S atoms.

[00269] The term "membered ring" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyl and thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[00270] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[00271] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH₂, -OH, -NH(CH₃), -N(CH₃)₂, -C0₂H, -C0₂alkyl, -C(=0)NH₂, -C(=0)NHalkyl, - C(=0)N(alkyl)₂, -S(=0)₂NH₂, -S(=0)₂NH(alkyl), -S(=0)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl, or -S(=0)₂alkyl. In some embodiments, an optional substituent is selected from halogen, -CN, -NH₂, -OH, -NH(CH₃), -N(CH₃)₂, -CH₃, -CH₂CH₃, -CF₃, - OCH₃, and -OCF₃. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.

[00272] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.

[00273] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.

[00274] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[00275] The term "antagonist," as used herein, refers to a molecule such as a compound, which diminishes, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists.

[00276] The term "LPA-dependent", as used herein, refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of LPA.

[00277] The term "LPA-mediated", as used herein, refers to refers to conditions or disorders that might occur in the absence of LPA but can occur in the presence of LPA.

[00278] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a compound (e.g. an LPA receptor antagonist described herein) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of an LPA receptor antagonist in a topical formulation described herein that is required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. [00279] The term "subject" or "individual" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[00280] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating at least one symptom of a disease disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[00281] The terms "prevent," "preventing," or "prevention" and other grammatical equivalents used herein include inhibiting (arresting or stopping) the development of a disorder and/or inhibiting (arresting or stopping) the further progression of a disorder. These terms are meant to include prophylaxis. For prophylactic benefit, the compositions are administered to an individual suspected of having a particular disorder, at risk of developing a disorder or to an individual reporting one or more symptoms of a disorder or at risk of reocurrence of a disease.

Formulations

[00282] Disclosed herein, in certain embodiments, is a formulation of a LPA1 receptor antagonist wherein the formulation is suitable for local administration or systemic administration.

[00283] In some embodiments, the formulation is an oral formulation. In some embodiments, the formulation is a parenteral (e.g., intravenous, subcutaneous, intramuscular) formulation. In some embodiments, the formulation is a topical formulation for administration to the eye.

[00284] Pharmaceutical formulations disclosed herein are formulated in any suitable manner. Any suitable technique, carrier, and/or excipient is contemplated for use with the LPA1 receptor antagonist. For a summary of pharmaceutical formulations described herein see Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Eighth Ed. (Lippincott Williams & Wilkins 2004), Muller, R.H. et al. Advanced Drug Delivery Reviews 59 (2007) 522-530, which are herein incorporated by reference for such disclosures.

Systemic Administration

[00285] In some embodiments, an LPA receptor antagonist is delivered to a target site in the eye of a mammal through systemic administration. In certain embodiments, a pharmaceutical formulations comprising an LPA receptor antagonist is optionally administered by multiple administration routes, including, but not limited to, oral and parenteral (e.g., intravenous, subcutaneous, intramuscular) routes of administration. Parenteral injections optionally involve bolus injections or continuous infusions. The pharmaceutical formulations, include, but are not limited to, solutions, suspensions, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, solid dosage forms, powders, immediate release formulation, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. Generally speaking, one will desire to administer an amount of an LPA1 receptor antagonist is that is effective to achieve a plasma level commensurate with the

concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect.

Oral Formulations

[00286] In certain embodiments, an LPA1 receptor antagonist is formulated in a manner that is suitable for oral administration to a mammal.

[00287] For oral administration, an LPA1 receptor antagonist is formulated by combining the active compound with pharmaceutically acceptable carriers or excipients. Such carriers enable the LPA1 receptor antagonist to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a mammal.

[00288] The pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and an LPA1 receptor antagonist as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.

[00289] The oral solid dosage formulations described herein include particles of an LPA1 receptor antagonist in crystalline form, amorphous form, semi-crystalline form, semi-amorphous form, or mixtures thereof.

[00290] In one embodiment, the pharmaceutical compositions described herein are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, solid oral dosage forms, fast melt formulations, lyophilized formulations, tablets, capsules, extended release formulations, IV formulations.

[00291] In one embodiment, an LPA1 receptor antagonist is formulated into an immediate release form that provides for once-a-day administration.

[00292] In some embodiments, the solid dosage forms described herein are in the form of a tablet, (including an immediate release tablet, an extended release tablet, a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, multiparticulate dosage forms, pellets, or granules.

[00293] In one embodiment, a capsule is prepared. In some embodiments, the formulations (nonaqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.

[00294] Liquid formulation dosage forms for oral administration include, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2^nd Ed., pp. 754-757 (2002).

Parenteral Formulations

[00295] Disclosed herein, in certain embodiments, is a formulation of a LPAl receptor antagonist wherein the formulation is suitable for parenteral administration.

[00296] In some embodiments, the LPAl receptor antagonist is formulated for intramuscular, subcutaneous, or intravenous injection. In some embodiments, the LPAl receptor antagonist is formulated as a suspension, solution or emulsion.

[00297] In some embodiments, the parenteral formulation comprises a pharmaceutically-acceptable excipient. In some embodiments, the parenteral formulation comprises a carrier, suspending agent, thickening agent, stabilizing agent, wetting agent, emulsifying agent, dispersing agent, preservative, antioxidant, buffer, an isotonizing agent, or a combination thereof.

[00298] Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00299] Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.

[00300] For intravenous injections, the LPAl receptor antagonist is optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.

[00301] Formulations for injection are optionally presented in unit dosage form (e.g., in ampoules or vials) or in multi dose containers. In some embodiments, a parenteral formulations is stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. [00302] In some embodiments, a parenteral formulation disclosed herein is formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

Topical formulations

[00303] In some embodiments, the topical formulations described herein locally antagonize LPA receptors in the epidermis, the dermis and/or the hypodermis of a mammal. In certain instances, localized dermal administration of an LPA receptor antagonist compound reduces or eliminates side- effects that are associated with systemic administration of an LPA receptor antagonist compound. Topical formulations include, but are not limited to, ointments, creams, lotions, solutions, pastes, gels, sticks, films, patches, bandages and wound dressings.

Creams and Lotions

[00304] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of a cream. In certain instances, creams are semisolid (e.g., soft solid or thick liquid) formulations that include an LPA receptor antagonist compound dispersed in an oil-in-water emulsion or a water-in-oil emulsion. Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of a lotion. In certain instances, lotions are fluid emulsions (e.g., oil-in-water emulsions or a water-in-oil emulsion). In some embodiments, the hydrophobic component of a lotion and/or cream is derived from an animal (e.g., lanolin, cod liver oil, and ambergris), plant (e.g., safflower oil, castor oil, coconut oil, cottonseed oil, menhaden oil, palm kernel oil, palm oil, peanut oil, soybean oil, rapeseed oil, linseed oil, rice bran oil, pine oil, sesame oil, or sunflower seed oil), or petroleum (e.g., mineral oil, or petroleum jelly).

[00305] In certain instances, lotions and creams have a "drying" effect on dermatological disorders (e.g., some or all fluid exuded from the disorder is miscible in the ointment) and are thus useful for dermatological disorders characterized by the exudation of fluids.

Ointments

[00306] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of an ointment. In certain instances, ointments are semisolid preparations that soften or melt at body temperature. In certain instances, ointments re-hydrate the skin and are thus useful for dermatological disorders characterized by loss of moisture.

Pastes

[00307] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of a paste. In certain instances, pastes contain at least 20% solids. In certain instances, pastes are ointments that do not flow at body temperature. In certain instances, pastes re-hydrate the skin and are thus useful for dermatological disorders characterized by loss of moisture. In certain instances, pastes serve as protective coatings over areas to which they are applied.

Gels and films

[00308] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of a gel. In certain instances, gels are semisolid (or semi-rigid) systems consisting of dispersions of large organic molecules dispersed in a liquid. In certain instances, gels are water-soluble and are removed using warm water or saline. In certain instances, gels re-hydrate the skin and are thus useful for dermatological disorders characterized by loss of moisture.

[00309] In certain instances, in the treatment of dermal lesions, contacting lesions with a dressing can often disturb injured tissues. The removal of many dressings for wounds such as burns surface lesions that involve a significant area of the skin can cause significant pain and often can re-open at least portions of partially healed wounds. In some instances, the topical formulations described herein are applied as a liquid to the affected area and the liquid gels as a film on the affected area. In some instances the film is a water soluble film and can be removed with water or a mild aqueous detergent, avoiding pain and discomfort associated with the removal of wound dressings. In certain instances, the topical formulation described herein is a dermal film comprising a flexible film made of a polyalkyloxazoline. In some instances, the film has a structural layer made of a

polyalkyloxazoline and a pressure sensitive adhesive layer that keeps the film in place.

Sticks

[00310] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is in the form of a stick. In certain instances, sticks are solid dosage forms that melt at body temperature. In some embodiments, a stick comprises a wax, a polymer, a resin, dry solids fused into a firm mass, and/or fused crystals. In some embodiments, a topical formulation of an LPA receptor antagonist compound is in the form of a styptic pencil (i.e., a stick prepared by (1) heating crystals until they lose their water of

crystallization and become molten, and (2) pouring the molten crystals into molds and allowing them to harden). In some embodiments, a topical formulation of an LPA receptor antagonist compound is in the form of stick wherein the stick comprises a wax (e.g., the wax is melted and poured into appropriate molds in which they solidify in stick form).

[00311] In some embodiments, a topical formulation of an LPA receptor antagonist compound is in the form of stick wherein the stick comprises a melting base (i.e., a base that softens at body temperature). Examples of melting bases include, but are not limited to, waxes, oils, polymers and gels. In some embodiments, a topical formulation of an LPA receptor antagonist compound is in the form of stick wherein the stick comprises a moisten base (i.e., a base that is activated by the addition of moisture).

Patches

[00312] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is administered via a patch. In some embodiments, a topical formulation disclosed herein is dissolved and/or dispersed in a polymer or an adhesive. In some embodiments, a film, a patch disclosed herein is constructed for continuous, pulsatile, or on demand delivery of an LPA receptor antagonist compound.

Wound Dressings

[00313] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is administered with (or via) a wound dressing. Wound dressings include, but are not limited to gauzes, transparent film dressings, hydrogels, polyurethane foam dressings, hydrocolloids and alginates. In certain instances, wound dressings promote wound healing. In some instances wound dressings reduce or inhibit aberrant wound healing.

Dermatological Excipients

[00314] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation comprises a penetration enhancer. Penetration enhancers include, but are not limited to, sodium lauryl sulfate, sodium laurate, polyoxyethylene-20- cetyl ether, laureth-9, sodium dodecylsulfate, dioctyl sodium sulfosuccinate, polyoxyethylene-9- lauryl ether (PLE), Tween 80, nonylphenoxypolyethylene (NP-POE), polysorbates, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium glycodihydrofusidate, oleic acid, caprylic acid, mono- and di-glycerides, lauric acids, acylcholines, caprylic acids, acylcarnitines, sodium caprates, EDTA, citric acid, salicylates, DMSO, decylmethyl sulfoxide, ethanol, isopropanol, propylene glycol, polyethylene glycol, glycerol, propanediol, and diethylene glycol monoethyl ether. In certain embodiments, the topical formulations described herein are designed for minimal systemic exposure and include, for example, low amounts of penetration enhancers. Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation comprises a gelling (or thickening) agent. In some embodiments, a topical formulation disclosed herein further comprises from about 0.1% to about 5%, from about 0.1% to about 3%, or from about 0.25% to about 2%, of a gelling agent. In certain embodiments, the viscosity of a topical formulation disclosed herein is in the range from about 100 to about 500,000 cP, about 100 cP to about 1 ,000 cP, about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP to about 8,000 cP, about 4,000 cP to about 10,000 cP, about 10,000 cP to about 50,000 cP. [00315] Suitable gelling agents for use in preparation of the gel topical formulation include, but are not limited to, celluloses, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, acacia (gum arabic), agar, aluminum magnesium silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan, cellulose, microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose, furcellaran, gelatin, ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, polyethylene glycol (e.g. PEG 200-4500), gum tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), or combinations thereof.

[00316] Gels include a single-phase or a two-phase system. A single-phase gel consists of organic macromolecules distributed uniformly throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecules and the liquid. Some single-phase gels are prepared from synthetic macromolecules (e.g., carbomer) or from natural gums, (e.g., tragacanth). In some embodiments, single-phase gels are generally aqueous, but will also be made using alcohols and oils. Two-phase gels consist of a network of small discrete particles.

[00317] Gels can also be classified as being hydrophobic or hydrophilic. In certain embodiments, the base of a hydrophobic gel consists of a liquid paraffin with polyethylene or fatty oils gelled with colloidal silica, or aluminum or zinc soaps. In contrast, the base of hydrophobic gels usually consists of water, glycerol, or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth, starch, cellulose derivatives, carboxyvinylpolymers, and magnesium-aluminum silicates).

[00318] Suitable agents for use in fomulations that are applied as liquids and gel upon application to the skin into a film include but are not limited to polymers composed of polyoxypropylene and polyoxyethylene that are known to form thermoreversible gels when incorporated into aqueous solutions. These polymers have the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful formulations that are applied as gels and/or films to the affected area. Examples of polymers that gel at body temperature and are used in gels and/or films described herein include and are not limited to poloxamers (e.g.,

PLURONICS F68®, F88®, F108®, and F127®, which are block copolymers of ethylene oxide and propylene oxide). The liquid state-to-gel state phase transition is dependent on the polymer concentration and the ingredients in the solution.

[00319] In some embodiments, the formulations and compositions disclosed herein are administered as a dermal paint. As used herein, paints (also known as film formers) are solutions comprised of a solvent, a monomer or polymer, an active agent, and optionally one or more pharmaceutically- acceptable excipients. After application to a tissue, the solvent evaporates leaving behind a thin coating comprised of the monomers or polymers, and the active agent. The coating protects active agents and maintains them in an immobilized state at the site of application. This decreases the amount of active agent which may be lost and correspondingly increases the amount delivered to the affected area of the skin of an individual. By way of non-limiting example, paints include collodions (e.g. Flexible Collodion, USP), and solutions comprising saccharide siloxane copolymers and a cross-linking agent. Collodions are ethyl ether/ethanol solutions containing pyroxylin (a nitrocellulose). After application, the ethyl ether/ethanol solution evaporates leaving behind a thin film of pyroxylin. In solutions comprising saccharide siloxane copolymers, the saccharide siloxane copolymers form the coating after evaporation of the solvent initiates the cross-linking of the saccharide siloxane copolymers.

[00320] In some instances, the topical formulations described herein comprise pressure sensitive adhesives (e.g., polyalkyloxazoline polymers) and allow for application of an adhesive film to an affected area of skin.

[00321] Disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation comprises an emollient. Emollients include, but are not limited to, castor oil esters, cocoa butter esters, safflower oil esters, cottonseed oil esters, corn oil esters, olive oil esters, cod liver oil esters, almond oil esters, avocado oil esters, palm oil esters, sesame oil esters, squalene esters, kikui oil esters, soybean oil esters, acetylated

monoglycerides, ethoxylated glyceryl monostearate, hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, methyl palmitate, decyloleate, isodecyl oleate, hexadecyl stearate decyl stearate, isopropyl isostearate, methyl isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate, oleyl myristate, oleyl stearate, and oleyl oleate, pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidic acid, behenic acid, erucic acid, lauryl alcohol, myristyl alcohol, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyl dodecanyl alcohol, lanolin and lanolin derivatives, beeswax, spermaceti, myristyl myristate, stearyl stearate, carnauba wax, candelilla wax, lecithin, and cholesterol. [00322] In certain embodiments, the topical formulations described herein comprise LPA receptor antagonists that are optionally incorporated within controlled release particles, lipid complexes, liposomes, nanoparticles, microspheres, microparticles, nanocapsules or other agents which enhance or facilitate localized delivery to the skin. An example of a conventional microencapsulation process for pharmaceutical preparations is shown in U.S. Pat. No. 3,737,337, incorporated herein by reference for such disclosure.

[00323] In some instances, a topical fomulation described herein is a liposomal formulation.

Liposomes are prepared by introducing an aqueous buffer into a mixture of phospholipid and organic solvent and the organic solvent is subsquently removed by evaporation under reduced pressure. An example of a liposomal preparation is described in Proc. Natl. Acad. Sci. 1978, 75, 4194-98, incorporated herein by reference for such disclosure. Liposomes are fractionated according to their particle sizes by size exclusion chromatography (SEC). The subfractions of liposomes are further sized by photon correlation spectroscopy (PCS) for their particle sizes. Enzymatic assays (e.g., phosphatidylcholine (PC) assay) are used to analyze lipid contents of liposomes.

[00324] In some instances a topical formulation described herein is an adhesive formulation having a viscosity suitable for application as a spray on a skin surface, and which forms a sustained drug- delivery adhesive solidified layer on the skin. The formulation comprises a propellant and a polymer that gels upon contact with the skin. The formulation is expelled out of a pressurized container and applied onto a skin surface as a layer. Additional steps include formation of a film on the skin surface by partial evaporation of the propellant and/or gellation of the polymer. The film on the skin dermally delivers the drug at a therapeutically effective rate over a sustained period of time. In some instances the topical formulation is sprayed on the skin in the form of a bioadhesive film.

[00325] In some embodiments, a topical formulation described herein is a solution, with water present in about 25% (w/w) to about 80% (w/w) water in the solution. In some embodiments, a topical formulation described herein is a cream, with water present in about 50% (w/w) to about 80% (w/w) water in the cream. In some embodiments, a topical formulation described herein is an ointment, with water present in about 1 % (w/w) to about 20% (w/w) water in the ointment.

[00326] In certain embodiments, a topical formulation comprising an LPA receptor antagonist compound compriss additional excipients such as, by way of example, abrasives, absorbents, anticaking agents, astringents, essential oils, fragrances, skin-conditioning agents, skin healing agents, skin protectants (e.g., sunscreens, or ultraviolet light absorbers or scattering agents), skin soothing agents, or combinations thereof.

[00327] Pharmaceutical topical formulations disclosed herein are formulated in any suitable manner. Any suitable technique, carrier, and/or excipient is contemplated for use with the LPA receptor antagonists disclosed herein. Methods of Dosing and Treatment Regimens

[00328] In one embodiment, LPAl receptor antagonists are used in the preparation of medicaments for the treatment of LPA-dependent or LPA-mediated diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one LPAl antagonist or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject.

[00329] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[00330] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[00331] In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").

[00332] For systemic modes of administration, generally speaking, one will desire to administer an amount of an LPAl antagonist is that is effective to achieve a plasma level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect. Doses employed for adult human treatment are typically in the range of 0.01mg-5000 mg per day or from about lmg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.

[00333] In some embodiments, formulations provide a therapeutically effective amount of an LPAl receptor antagonist, or a pharmaceutically acceptable salt thereof, enabling, for example, once a week, twice a week, three times a week, four times a week, five times a week, once every other day, once-a-day, twice-a-day (b.i.d.), or three times a day (t.i.d.) administration if desired. In one embodiment, the formulation provides a therapeutically effective amount of an LPAl receptor antagonist, or a pharmaceutically acceptable salt thereof, enabling once-a-day administration.

[00334] Also disclosed herein, in certain embodiments, is a topical formulation of an LPA receptor antagonist compound wherein the topical formulation is administered for prophylactic and/or therapeutic treatments. In certain instances, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the individual's health status and response to the drugs, and the judgment of the treating physician. In some embodiments, the dose of an LPA receptor antagonist is about 0.001% by weight to about 10% by weight of the topical formulation. In some embodiments, the dose of an LPA receptor antagonist is about 0.001% by weight to about 5% by weight of the topical formulation.

[00335] In some embodiments, where a dermatological disorder does not improve, a topical formulation disclosed herein is administered chronically (i.e., for an extended period of time, including throughout the duration of the individual's life). In some embodiments, where a dermatological disorder does improve, a topical formulation disclosed herein is given continuously; alternatively, the dose of active agent being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In some embodiments, a drug holiday lasts between 2 days and 1 year, including all integers in between. In some embodiments, the dose reduction during a drug holiday is from about 10% to about 100%, including all integers in between.

[00336] In some embodiments, where a dermatological disorder does improve, a topical formulation disclosed herein is administered as a maintenance dose. In some embodiments, where a

dermatological disorder does improve, a topical formulation disclosed herein is administered with reduced frequency or at a reduced dose.

[00337] In one embodiment, a topical formulation disclosed herein is formulated for controlled release of an LPA receptor antagonist. In some embodiments, an LPA receptor antagonist is released over a time period exceeding 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or 1 year.

Patient Selection

[00338] In any of the aforementioned aspects involving the prevention or treatment of LPA-mediated diseases or conditions of the eye are further embodiments comprising identifying patients by screening for LPA receptor gene SNPs. Patients can be further selected based on increased LPA receptor expression in the tissue of interest. LPA receptor expression are determined by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some embodiments, patients are selected based on the concentration of serum or tissue LPA measured by mass spectrometry. In some embodiments, patients are selected based on a combination of the above markers (increased LPA concentrations and increased LPA receptor expression).

Combination Therapy

[00339] In certain instances, it is appropriate to administer at least one LPA1 receptor antagonist in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Or in another example, a patient is presented with a situation in which antagonism of LPA receptors provides potential harm, for example, if the patient is wounded, antagonism of LPA receptors may lead to a delay in wound healing. In such an event, in certain embodiments, the patient benefits by administration of a local wound-healing agent (at the site of the wound) in combination with the co-existing administration of a LPA 1 receptor antagonist.

[00340] Or, in one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant {i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[00341] In one specific embodiment, a LPA1 receptor antagonist is co-administered with a second therapeutic agent, wherein the LPA1 receptor antagonist and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[00342] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[00343] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.

Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens can be determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a LPA1 receptor antagonist is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a LPA1 receptor antagonist and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [00344] Compositions and methods for combination therapy are provided herein. In accordance with one aspect, the pharmaceutical compositions disclosed herein are used to treat LPA-dependent or LPA-mediated conditions.

[00345] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors. These factors include the disease, disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[00346] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[00347] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms. In one embodiment, one of the therapeutic agents is given in multiple doses, and in another, two (or more if present) are given as multiple doses. In some embodiments of non-simultaneous administration, the timing between the multiple doses vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.

[00348] The LPA1 receptor antagonist and combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years. [00349] By way of example, therapies which combine a LPAl receptor antagonist with inhibitors of LPA synthesis or LPA receptor antagonists, either acting at the same or other points in the LPA synthesis or signalling pathway, are encompassed herein for treating LPA-dependent or LPA- mediated diseases or conditions.

[00350] In one aspect, pharmaceutical compositions and methods disclosed herein include an additional therapeutic agent. In one aspect, the additional therapeutic agent is a therapeutic agent other than a LPAl antagonist.

[00351] In one aspect, the pharmaceutical compositions disclosed herein that include a LPAl receptor antagonist are co-administered with (either separately or in the same formulation) an antibiotic. Antibiotics include, but are not limited to, polymyxin B sulfate / bacitracin zinc, polymyxin B / neomycin / gramicidin, polymyxin B/trimethoprim, polymyxin B/bacitracin, fluoroquinolones (e.g., ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, levofloxacin), aminoglycosides (e.g. tobramycin, azithromycin, gentamicin, erythromycin, bacitracin.

[00352] In one aspect, the pharmaceutical compositions disclosed herein that include a LPAl receptor antagonist are co-administered with (either separately or in the same formulation) a leukotriene modulator. Leukotriene modulators include, but are not limited to, 5-lipoxygenase inhibitors (5-LO) inhibitiors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds, LTA₄ hydrolase inhibitors, leukotriene receptor antagonist (e.g. CysLTi receptor antagonists, BLTiR antagonists).

[00353] In some embodiments, the LPAl receptor antagonist is co-administered with (either separately or in the same formulation) an antiviral agent. Antiviral agents include, but are not limited to, acyclovir, vidarabine, trifluridine.

[00354] In some embodiments, the LPAl receptor antagonist is co-administered with (either separately or in the same formulation) cyclosporine.

[00355] In some embodiments, the LPAl receptor antagonist is co-administered with (either separately or in the same formulation) a leukotriene modulator. Leukotriene modulators include, but are not limited to 5-lipoxygenase (5-LO) inhibitors inhibitors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds and leukotriene receptor antagonist (e.g. CysLTi receptor antagonists).

[00356] In some embodiments, a LPAl receptor antagonist is used to treat or reduce fibrosis in a mammal. In some embodiments, a LPAl antagonist is administered in combination with one or more immunosuppresants. Immunosuppressive therapy is clinically used to treat or prevent the rejection of transplanted organs and tissues; treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e.g. scleroderma/systemic sclerosis, rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, psoriasis, Crohn's disease, and ulcerative colitis); treatment of some other non-autoimmune inflammatory diseases, and in the treatment of fibrotic conditions. [00357] In some embodiments, a LPA1 receptor antagonist is adminsitered with corticosteroids. In some embodiments, a LPA1 antagonist is adminsitered with an a therapeutic agent selected from among: Calcineurin inhibitors (such as, but not limited to, cyclosporin, tacrolimus); mTOR inhibitors (such as, but not limited to, sirolimus, everolimus); anti-proliferatives (such as, but not limited to, azathioprine, mycophenolic acid); corticosteroids (such as, but not limited to, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, hydrocortisone); antibodies (such as, but not limited to, monoclonal anti-IL-2Ra receptor antibodies (basiliximab, daclizumab), polyclonal anti-T-cell antibodies (anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)), B-cell antagonists, rituximab, natalizumab.

[00358] Other therapeutic agents include, but are not limited to: cyclophosphamide, penicillamine, cyclosporine, nitrosoureas, cisplatin, carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues, protein synthesis inhibitors, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, Atgam^, Thymoglobuline^®, OKT3^®, basiliximab, daclizumab, cyclosporin, tacrolimus, sirolimus, Interferons (IFN-β, IF -γ), opioids, TNF binding proteins (infliximab, etanercept, adalimumab, golimumab), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, rapamicin, mycophenolic acid, mycophenolate mofetil, FTY720, as well as those listed in US 7,060,697.

[00359] In one embodiment, a LPA1 antagonist is administered in combination with Cyclosporin A (CsA) or tacrolimus (FK506). In one embodiment, a LPA1 antagonist is administered to a mammal in combination with an anti-inflammatory agent including, but not limited to, non-steroidal antiinflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).

[00360] NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L- 745,337 and NS398).

[00361] Corticosteroids, include, but are not limited to: betamethasone, prednisone, alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone,

difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, halcinonide, halometasone, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone,

meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, and ulobetasol.

[00362] In one embodiment, a LPAl receptor antagonist is administered in combination with leukotriene receptor antagonists including, but are not limited to, BAY u9773 (see EP 00791576; published 27 Aug 1997), DUO-LT (Tsuji et al, Org. Biomol. Chem., 1 , 3139-3141, 2003), zafirlukast, montelukast, prankulast, and derivatives or analogs thereof.

[00363] In some embodiments, an LPAl receptor antagonist is administered in combination with agents to increase blood flow, including nifedipine, amlodipine, diltiazem, felodipine, or nicardipine.

[00364] In some embodiments, an LPAl receptor antagonist is administered in combination with d- penicillamine, colchicine, PUVA (Psoralen + UVA treatment), Relaxin, or cyclosporine.

[00365] In some embodiments, an LPAl receptor antagonist is administered in combination with methotrexate, cyclophosphamide, azathioprine, or mycophenolate.

[00366] In some embodiments, the LPAl antagonist and the additional therapeutic agent are in the same pharmaceutical composition. In some embodiments, the LPAl receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions. In some embodiments, the LPAl receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions wherein the LPAl receptor antagonist is administered topically or orally and the additional therapeutic agent is administered by the same route or by a different route. In some embodiments, the LPAl receptor antagonist and the additional therapeutic agent are administered at the same time. In some embodiments, the LPAl receptor antagonist and the additional therapeutic agent are administered at different times.

EXAMPLES

[00367] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

Example 1; Topical solution formulation that forms film

[00368] Poloxamer 407 is mixed in water at temperature below room temperature. LPAl receptor antagonist and excipients are added and the mixture is packaged in sterile bottles.

Example 2; Topical gel formulation with preservative LPAl receptor antagonist 0.5% w/w

Methyl paraben 0.1% w/w

EDTA 0.1% w/w

Carbomer 934 2%

Citrate buffer To pH 7

Sterile water ~ 30% w/w

Propylene glycol 60% w/w

Transcutol 10% w/w

[00369] Carbomer 934 is stirred in water. LPAl receptor antagonist and other excipients are added to the mixture and the mixture is packaged in sterile tubes.

Example 3: Topical cream formulation with preservative

[00370] LPAl antagonist is suspended in water, Span 85 is added followed by addition of glycerin, mineral oil and other excipients and the mixture is packaged in sterile tubes.

Example 4; Topical liposomal gel formulation

[00371] Liposomes with LPAl receptor antagonist are prepared using methods described in e.g., US Patent No. 6,355,267. The optimum ratio of the components is determined. The liposomes are characterized for their vesicle size, shape, encapsulation efficiency, % drug content and incorporated into a gel base. The formulation is packaged in sterile tubes.

Example 5; Ointment Compositions

[00372] A non-limiting example of an ointment composition is presented below.

Example 6; Gel Compositions

[00373] A non-limiting example of a gel composition is presented below.

Example 7; Cream Compositions

[00374] A non-limiting example of a cream composition is presented below.

Example 8; Oral Solution [00375] An oral solution is prepared at 20 mg/mL of LPAl receptor antagonist. In one embodiment, an oral pharmaceutical composition is prepared with the following ingredients:

- 20 mg/mL of LPAl receptor antagonist

- aqueous 1 OmM Na₂C0₃

- 20% propylene glycol

[00376] The manufacturing process for the oral solutions of LPAl receptor antagonist described above is as follows: weigh the required amount of sodium carbonate and transfer to the container. Add the required amount of water to make a lOmM solution and mix until dissolved. Weigh the required amount of propylene glycol and add this to the solution and mix until homogenous. Weigh the required amount of LPAl antagonist and slowly add to the solution. Mix until all LPAl receptor antagonist is dissolved (sonicate, warm, or stir if necessary).

Example 9: Capsule Formulation

[00377] In one embodiment, a capsule formulation of LPAl receptor antagonist for administration to humans is prepared with the following ingredients:

[00378] The process to prepare LPAl antagonist in a capsule is as follows: Weigh the required amount of LPAl antagonist, add into the appropriate size capsule, and close capsule.

Example 10: Tablet Formulation

[00379] Non-limiting examples of immediate release tables that include either LPAl receptor antagonist are presented below.

[00380] All excipients (except lubricant) are added to a V-shell blender. Add LPAl receptor antagonist to the V-shell blender. Mix in the V-shell blender for approximately 15 minutes. Add lubricant and blend for 2 minutes. Tablet cores are compressed with a suitable press. During compression, individual and average tablet weight, hardness, thickness, and friability are monitored

Example 11: Parenteral Composition

[00381] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, and the like), 100-1000 mg of a water-soluble compound ofLPAl receptor antagonist (or water soluble salt thereof) is dissolved in sterile water and then mixed with 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection

[00382] In another embodiment, the following ingredients are mixed to form an injectable formulation: 1.2 g of a compound of LPA1 receptor antagonist, 2.0 mL of sodium acetate buffer solution (0.4 M), HC1 (1 N) or NaOH (1 M) (q.s. to suitable pH), water (distilled, sterile) (q.s.to 20 mL). All of the above ingredients, except water, are combined and stirred and if necessary, with slight heating if necessary. A sufficient quantity of water is then added.

Example 12. Establishment of a CHO Cell Line Stably Expressing Human LPA^

[00383] A 1.1 kb cDNA encoding the human LPA_t receptor was cloned from human lung. Human lung RNA (Clontech Laboratories, Inc. USA) was reverse transcribed using the RETROscript kit (Ambion, Inc.) and the full-length cDNA for human LPAi was obtained by PCR of the reverse transcription reaction. The nucleotide sequence of the cloned human LPAi was determined by sequencing and confirmed to be identical to the published human LPAi sequence (An et al.

Biochem. Biophys. Res. Commun. 231 :619 (1997). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPAi were selected using hygromycin and identified as cells that show Ca-influx in response to LPA.

Example 13. Generation of Cells Transiently Expressing Human hLPA?

[00384] An expression vector encoding thehuman LPA₂ cDNA was transiently transfected into B103 cells using Lipofectamine™ 2000 (Invitrogen) following the manufacturers instruction. On the day before the assay, 30,000-35,000 cells/well were seeded together with 0.2 μΐ lipofectamine 2000 and 0.2 μg human LPA2 expression vector in 96-well Poly-D-Lysine coated black-wall clear-bottom plates (BD BioCoat) in DMEM + 10% FBS. Following an overnight culture, cells were washed once with PBS then cultured in serum-free media for 4 hours prior to start of the calcium flux assay.

Example 14. Establishment of a CHO Cell Line Stably Expressing Human LPA₃

[00385] A vector containing the human LPA₃ receptor cDNA was obtained from the Missouri S&T cDNA Resource Center (www.cdna.org). The full-length cDNA fragment for human LPA₃ was obtained by PCR from the vector. The nucleotide sequence of the cloned human LPA₃ was determined by sequencing and confirmed to be identical to the published human LPA₃ sequence (NCBI accession number NM 012152). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA₃ were selected using hygromycin and identified as cells that show Ca- influx in response to LPA.

Example 15. LPAI and LPA3 Calcium Flux Assays. [00386] Human LPA_! or LPA₃ expressing CHO cells are seeded at 20,000-45,000 cells per well in a 96-well poly-D-lysine coated plate one or two days before the assay. Prior to the assay, the cells are washed once with PBS and then cultured in serum-free media for at least 6 hrs and up to 24hrs . On the day of the assay, a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca²⁺ and Mg²⁺ and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 1 hour at room temperature. 10 μΐ of test compounds in 2.5% DMSO are added to the cells and incubation continued at room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca²⁺ measured using the Flexstation 3 (Molecular Devices). IC₅₀s are determined using Symyx Assay Explorer analysis of drug titration curves.

Example 16. LPA2 Calcium Flux Assay.

[00387] LPA2 calcium flux is measured using at least one of two different assays. In one assay, BT- 20 human breast cancer cells are seeded at 25,000-35,000 cells per well in 150 μΐ complete media on Poly-D-Lysine coated black-wall clear-bottom plates. Following an overnight culture, cells are washed once with PBS then serum starved for 4-6 hours prior to the assay. On the day of the assay, a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca²⁺ and Mg²⁺ and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 15 minutes at 37°C. 25 μΐ of test compounds in 2.5% DMSO are added to the cells and incubation continued at 37°C for 15-30 minutes. Cells are the stimulated by the addition of 100 nM LPA and intracellular Ca²⁺ measured using the Flexstation 3 (Molecular

Devices). IC₅₀s are determined using Symyx Assay Explorer analysis of drug titration curves In the second assay, B 103 cells transiently expressing huma LPA2 are serum starved for 4 hours. A calcium indicator dye (Calcium 4, Molecular Devices) in assay buffer (HBSS with Ca²⁺ and Mg²⁺ and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is then added to each well and incubation continued for 1 hour at 37°C. 10 μΐ of test compounds in 2.5% DMSO are added to the cells and incubation continued at room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca²⁺ measured using the Flexstation 3 (Molecular Devices). IC₅₀S are determined using Symyx Assay Explorer analysis of drug titration curves.

Example 17. GTPYS Binding Assay

[00388] The ability of a compound to inhibit binding of GTP to LPAi is assessed via a membrane

[³⁵S] -GTPyS binding assay. CHO cells stably expressing the recombinant human LPAi receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000 xg to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol. Membranes (-25 μg per well) are incubated in 96-well plates with 0.1 nM [³⁵S]- GTPyS, 900 nM LPA, 5 μΜ GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 10 mM MgCl₂ , 50 μg/ml saponin and 0.2% fatty-acid free human serum albumin) for 30 minutes at 30°C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates. The filter plates are washed 3 times with 1 ml cold Wash Buffer (50 mM Hepes, 7.5, 100 mM NaCl and 10 mM MgCl₂) and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (900 nM LP A). IC₅₀S were determined using Graphpad prism analysis of drug titration curves.

[00389] Illustrative in vitro biological data is presented in the Table below.

A= less than 0.2μΜ , B= 0.2-1.0μΜ, and C= greater than ΙμΜ; ND = assay not performed

Example 18. LPAI Chemotaxis Assay.

[00390] Chemotaxis of the A2058 human melanoma cells was measured using the Neuroprobe

ChemoTx® System plates (8 μιη pore size, 5.7 mm diameter sites). The filter sites were coated with 0.001% fibronectin (Sigma) in 20 mM Hepes, pH 7.4 and allowed to dry. A2058 cells were serum- starved for 24 hours , then harvested with Cell Stripper and resuspended in DMEM containing 0.1% fatty-acid-free bovine serum albumin (BSA) to a concentration of 1 x 10⁶/ml. Cells were mixed with an equal volume of test compound (2X) in DMEM containing 0.1% fatty- acid- free BSA and incubated at 37°C for 15 minutes. LP A (100 nM in DMEM containing 0.1% fatty-acid-free BSA) or vehicle was added to each well of the lower chamber and 50 μΐ of the cell suspension/test compound mix was applied to the upper portion of the ChemoTx plate. Plates were incubated at 37°C for three hours and then the cells removed from the upper portion by rinsing with PBS and scraping. The filter was dried then stained with HEMA 3 Staining System (Fisher Scientific). The absorbance of the filter was read at 590 nM and IC₅₀S were determined using Symyx Assay Explorer.

[00391] In this experiment, Compound A inhibited LPA-driven chemotaxis (IC₅₀ less than 300 nM) of human A2058 melanoma cells.

[00392] In this experiment, compound B inhibited LPA-driven chemotaxis (IC₅₀ less than 100 nM) of human A2058 melanoma cells.

Example 19; Mouse dermal vascular leak assay

[00393] Female BALB/c mice (Harlan) weighing 20-25 grams were given free access to standard mouse chow and water and were allowed to acclimate for two weeks prior to study initiation.

Compound 1 was prepared in water vehicle at a concentration of 3 mg/ml and delivered by oral gavage at a volume of 10 ml/kg to yield a dose of 30 mg/kg. Three hours following dose, mice were placed into a restraining device and given Evan's blue dye intravenously by tail vein injection (0.2 ml of a 0.5 % solution). Mice were then anesthetized using 3% isoflurane anaesthesia to allow for intradermal injection of LP A (30 g in 20 μΐ 0.1 % fatty acid free BSA). Thirty minutes after LPA injection mice were sacrificed by CO₂ inhalation and the skin removed from the challenge site and placed into 2 ml formamide for overnight extraction of Evan's blue dye.

[00394] Following extraction, a 150 μΐ aliquot of formamide for each tissue sample was placed into a 96 well plate and read at 610 nm using a photospectometer. The resulting data (OD units) were plotted using GraphPad Prizm. In this experiment Compound B reduced LPA-induced Evan's blue dye leak into the skin.

Example 20; Mouse Model of Bleomycin-Induced Scleroderma

[00395] A mouse model of bleomycin-induced scleroderma was used to evaluate the effect of compounds A and B in skin fibrosis. Methods were adapted from (Yamamoto, T et al. The Journal of Investigative Dermatology, 1 12: 456-462, 1999). Female C57B1/6 mice were anesthetized with isoflurane (3.0-3.5% in 100% 0₂) and two areas shaved bilaterally on the lower dorsolateral region. BLM (1 - 10 μg in 100 μΐ) prepared in sterile filtered PBS was administered subcutaneously to each shaved region once daily for 5 to 7 days per week for a total of 4 weeks (28 days).

[00396] Compound A and Compound B were prepared in water vehicle and delivered orally twice a day on weekdays and once daily on weekends.

[00397] On day 28 all animals were sacrificed. The dorsolateral skin removed, trimmed of adherent subcutaneous fat and an 8 mm biopsy punch was used to collect two skin samples from each ,subject. One sample submerged in 10% neutral buffered formalin and submitted for histological analysis. The second sample was frozen at -80°C for further processing of collagen content using either Sircol or hydroxyproline methods.

[00398] FIGURE 1 and 2: Results of assay on mouse model of bleomycin-induced scleroderma using Compound A. FIGURE 1 shows dermal thickness. FIGURE 2 shows collagen content.

*P<0.05 versus vehicle group, t-test. Compound A reduced both the dermal thickness and collagen content.

[00399] FIGURE 3 and 4: Results of assay on mouse model of bleomycin-induced scleroderma using Compound B. FIGURE 3 shows dermal thickness. FIGURE 4 shows collagen content.

#P<0.05 versus PBS; *P<0.05 versus BLM; ANOVA. Compound B reduced both the dermal thickness and collagen content.

Example 21: Clinical Trial in Humans with Keloids

[00400] The purpose of this study is to evaluate potential efficacy of topical formulations that include at least one LPAl receptor antagonist in the treatment of keloids following single daily applications of three different topical formulations that include a LPAl receptor antagonist (0.1 % gel, ointment and liquid) and a comparable control (propylene glycol). In addition, the pain and/or tolerability (itching, local irritation) of the application of each formulation will also be assessed. Data from this clinical study may be used to select a formulation for further clinical evaluation.

Study protocol:

[00401] This is a randomized, controlled, single-blind, single-center, Phase 2 study in twenty volunteers. Each subject will have a single 15 minute exposure to each of three topical LPA1 antagonist formulations and the control in a 24 hour period. Each application site will be 1.0 x 1.0 cm in size. The dose applied will be 15 μg per cm² and hence the total dose applied will be 15 μg. Treatment will be continued for a period of three weeks.

Eligibility:

[00402] Have keloid lesions of at least 1.0 x 1.0 cm size. Agree not to use topically-applied products containing non-steroidal anti-inflammatory drugs, menthol, methyl salicylate, other counterirritants, local anesthetics, steroids or capsaicin for the duration of the study.

Exclusion Criteria:

[00403] Any dermatological condition(s) other than keloids that in the judgment of the Principal

Investigator has the potential to disrupt skin integrity. Any skin infection, skin irritation (e.g., poison oak), history of eczema, trauma or burn (including sunburn) on the skin within 30 days preceding the Application Visit (Day 0). Use of any systemic medications within 30 days prior to the Application Visit (Day 0). Use of any topically-applied product including prescription or over the-counter (OTC) analgesic creams/lotions/patches, non steroidal anti-inflammatory drugs, counterirritants, local anesthetics, steroids or capsaicin within 30 days preceding the Application Visit (Day 0).

Primary outcome measure

[00404] Reduction in itching and/or pain at sites of lesions. A global assesment at day 7, 14 and 21 will be carried out by the attending physician.

Secondary outcome measure

[00405] Improvement in quality of life for patients. Improvement in quality of sleep at day 0 and day 21.

Example 22; Clinical Trial in Humans with Raynaud's Phenomenon

[00406] This interventional phase 2 study will evaluate the safety, tolerability and efficacy of a liposomal gel formulation that includes a LPA1 antagonist in treatment of patients that have Raynaud's symptoms. Patients will apply 0.1% liposomal gel formulation of a LPA1 receptor antagonist to the hands twice a day for 3 weeks. Patients fingers will be monitored for changes in blood flow and skin temperature. Symptoms of pain, tingling and numbness will also be monitored. Study Design:

[00407] This study will be a Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Safety/Efficacy Study in Adult Patients suffering from Raynaud's Phenomenon. Eligibility:

[00408] Patients of ages 18 years to 75 years, both men and women, that have a clinical diagnosis of Raynaud's or symptoms with reduced blood flow as measured using laser Doppler equipment. Patients will have discontinued any vasodilator therapies for at least 4 weeks prior to enrollment in the study and no vasodilator medications will be prescribed during the course of the study. Women must have proof of a negative pregnancy test prior to study start and both men and women will agree to use effective birth control throughout.

Exclusion Criteria:

[00409] Concurrent use of and vasodilator medications; patients with a history of an unstable medical condition or any current condition that would interfere with the present study; and patients that have undergone major surgery within 6 months of the first study treatment or patients with open skin lesions or skin conditions where the topical drug is to be applied.

Protocol

[00410] Treatments are applied twice daily over the hands, for a 3 weeks.

Primary Outcome Measures:

[00411] Changes in blood flow in the fingers of the non-dominant hand following exposure to cold temperature over a timeframe of 130 minutes.

Secondary Outcome Measures:

[00412] Reduction in skin temperature recovery time and symptoms observed in the fingers of the non-dominant hand following the induction of constriction of blood vessels resulting from exposure to cold temperature over a timeframe of 130 minutes. Also the frequency and severity of adverse events.

Example 23; Rabbit Wound Healing and Hypertrophic Scar Model

[00413] Following anesthesia, ear wounds are created in 10 young adult female New Zealand rabbits, 4 wounds per ear on each ear for a total of 8 wounds per animal. Wounds were created using a 7-mm biopsy punch with the wound created to go to bare cartilage. A dissecting microscope is used to ensure complete removal of the epidermis, dermis and perichondrium in each wound. For the hypertrophic scar model, it is the removal of the perichondrial layer and subsequent delay in reepithelialization of the defect that results in the elevated scar. Each wound heals independently and is considered a separate sample.

[00414] Two treatment groups are examined to study the early phase and a later phase of wound healing. The early treatment group (n=15 rabbits, 120 wounds) are treated with either the test compound formulated as a 0.05 - 1.5% by weight topical formulation (solution, cream, ointment or gel) or placebo using the topical vehicle formulation post-wounding on days 0, 1 , 2, 3, 4, 5, 6 and 7 and harvested on day 28 after wounding. The later treatment group (n=15 rabbits, 120 wounds) are treated with either the test compound formulated as a 0.05 - 1.5% topical formulation (solution, cream, ointment or gel) or placebo using the topical vehicle formulation post-wounding on days 7, 8, 9, 10, 11 , 12, 13 and 14 and harvested on day 28 after wounding. Half ofthe wounds in each group are treated with active compound and half are treated with placebo. Each wound is covered with a sterile dressing (Tegaderm; 3M) and dressings are changed daily following each treatment and as needed until the wound appears reepithelialized on gross examination. Wounds are excluded from analysis if there is evidence of infection, desiccation or necrosis.

[00415] At the end of each study wounds are harvested with a 5-mm margin of surrounding unwounded tissue. The scars are bisected and half of each wound is fixed in 4% neutral-buffered formaldehyde, dehydrated, embedded in paraffin, cut in 4-μηι sections, and stained with Masson's trichrome or sirrus red. The other half of each wound is flash frozen in liquid nitrogen and stored for RNA extraction

Histologic Analysis

[00416] Light microscopy is used to examine each tissue section and the degree of wound healing and scar hypertrophy are measured with a calibrated lens reticle in a blinded fashion. Wound healing parameters: Relevant measurements are granulation tissue ingrowth volume and height, wound epithelialization, and wound closure. Each parameter is assessed twice and the results are averaged.

[00417] Scar hypertrophy parameters: The scar elevation index is determined as described by Lu et al, J. Am. Coll. Surg., 2005, 201, p391-397. The values are determined twice by in a blinded fashion and the results averaged.

[00418] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope ofthe appended claims.

Claims

WHAT IS CLAIMED IS:

1 A topical formulation comprising an LPAl receptor antagonist and at least one suitable pharmaceutically acceptable excipient, wherein the topical formulation is suitable for administration to the skin of a mammal.

2. The topical formulation of claim 1 , wherein the LPAl receptor antagonist is in an amount effective for the treatment of a dermal disease or condition.

3 The topical formulation of claim 1 or claim 2, wherein the topical formulation is an

ointment, cream, lotion, paste, gel, stick, a film, a patch or wound dressing.

4. The topical formulation of any one of claims 1-3, wherein the LPAl receptor antagonist is a compound having

Formula (I)

wherein

C(=0)NHS0₂CH₃, or -C(=0)NHS0₂CH₂CH₃; R^D is -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, - CH(CH₃)₂, -CH₂CH₂CH₂CH₃, or -C(CH₃)₃;

L¹ is Ci-C₄alkylene or C₃-Cecycloalkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃;

R⁸ is H or -CH₃;

CY is Ci-Cealkyl, substituted or unsubstituted C₃-Cecycloalkyl, or substituted or

unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, Br, I, -OH, -CN, C C₄alkyl, Ci-C₄fluoroalkyl, C

C₄fluoroalkoxy, or Ci-C₄alkoxy;

5. The topical formulation of claim 4, wherein the compound of Formula (I) has the structure of Formula (II): N H

Formula (II)

wherein,

n is 0, 1, or 2.

6. The topical formulation of claim 4 or claim 5, wherein:

L¹ is -CH₂-, or cyclopropyl-l ,l-diyl;

R³ is H or -CH₃;

R⁸ is -C¾.

7. The topical formulation of claim 4, wherein the LPAl receptor antagonist is:

(R)-2-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A):

(R)-l-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4- yl)cyclopropanecarboxylic acid (Compound B):

(R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl-4- yl)acetic acid (Compound C):

{5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4- yl}-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound D):

1 -(4'- {4-[(R)- 1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl} -biphenyl- 4-yl)-cyclopropanecarboxylic acid (Compound E):

l- {4'-[4-((R)-l-Phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}- cyclopropanecarboxylic acid (Compound F):

(3-Methyl-5-{4'-[l-(5-oxo-2,5-dihydro-[l ,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl}- isoxazol-4-yl)-carbamic acid (R)-l -phenyl-ethyl ester (Compound G):

(3-Methyl-5- {4'-[ 1 -(lH-tetrazol-5-yl)-cyclopropyl]-biphenyl-4-yl} -isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound H);

or a pharmaceutically acceptable salt thereof.

8. The topical formulation of any one of claims 1-3, wherein the LPAl receptor antagonist has structure of Formula (III):

Formula (III)

wherein

R¹ is -CO₂H, -C0₂R^D, tetrazolyl, 5-oxo-2,5-dihydro-[l ,2,4]oxadiazol-3-yl, -

C(=0)NHS0₂CH₃, or -C(=0)NHS0₂CH₂CH₃; R^Dis -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, - CH(CH₃)₂, -CH₂CH₂CH₂CH₃, or -C(CH₃)₃;

L¹ is absent, or a CpCgalkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃;

R⁴ is -NHC(=0)OCH(R⁸)-CY;

R⁸ is H, or -CH₃;

CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, Br, I, -OH, -CN, C_r C₄alkyl, Ci-C₄fiuoroalkyl, Ci-C₄iluoroalkoxy, or Ci-C₄alkoxy;

9. The topical formulation of claim 8, wherein:

R¹ is -C0₂H or -C0₂R^D;

L¹ is -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH₂CH₂-, -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, - CH₂CH₂CH₂-, or -CH₂CH₂CH₂CH₂-;

R³ is H or -CH₃;

R⁸ is -CH₃.

10. The topical formulation of claim 8, wherein the LPAl receptor antagonist is 6-(4-{4-[l-(2- Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hex-5-ynoic acid, or 7-(4-{4-[l-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)- hept-6-ynoic acid, or a pharmaceutically acceptable salt thereof.

11. The topical formulation of any one of claims 1-3, wherein the LPAl receptor antagonist has the structure of Formula (VI):

Formula (VI)

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, or tetrazolyl;

R^D is H or Ci-C₆alkyl;

R^E is Ci-C₆alkyl, C₃-C₆cycloalkyl, or substituted or unsubstituted phenyl;

L³ is a substituted or unsubstituted C₃-C₆alkylene, a substituted or unsubstituted C₃-

Cgfluoroalkylene, or a substituted or unsubstituted C₃-Cgheteroalkylene, where if L³ is substituted then L is substituted with 1 , 2 or 3 R ; each R is independently F, C_r

C₄alkyl, Ci-C₄iluoroalkyl, or -OH;

each R^c is independently halogen, -CN, -N0₂, -OH, C_rC₄alkyl, Ci-C₄fluoroalkyl, C_r

C₄fluoroalkoxy, Ci-C₄alkoxy, or C[-C₄heteroalkyl;

R³ is H or Ci-C₄alkyl;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

12. The topical formulation of claim 1 1 , wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or C C₄alkyl;

R^E is Ci-C₄alkyl;

L³ is a substituted or unsubstituted C3-C₄alkylene, a substituted or unsubstituted C₃-

C fluoroalkylene, or a substituted or unsubstituted C₃-C₆heteroalkylene; where if L³ is substituted then L³ is substituted with 1, 2 or 3 R¹³; each R¹³ is independently selected from F, -CH₃, -CH₂CH₃, -CF₃, and -OH;

R³ is -H, -CH₃ or -CH₂CH₃.

13. The topical formulation of any one of claims 1-3, wherein the LPAl receptor antagonist has the structure of Formula (VII):

Formula (VII)

wherein,

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, -CN, or tetrazolyl;

R^Dis H or Ci-C₆ alkyl;

R^E is C C₆ alkyl or a substituted or unsubstituted phenyl;

L² is absent, -C(=0)-, -N(R^D)-, substituted or unsubstituted C C₄ alkylene, or substituted or unsubstituted Ci-C₄ heteroalkylene, where if L² is substituted, then L² is substituted with R¹², where R¹² is F, C C₄alkyl, -OH, or -0R^D;

ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R¹⁴, each R¹⁴ is independently selected from halogen, -CN, -OH, Ci-C₄alkyl, Cp C fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, and Ci-C heteroalkyl; L is absent, or a substituted or unsubstituted C C₄ alkylene, where if L is substituted then

L⁴ is substituted with R¹³, where R¹³ is F, Ci-C₄alkyl, -OH, or -OR^D;

R³ is H or C C₄ alkyl;

Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The topical formulation of claim 13, wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or C C₄ alkyl;

R^E is Ci-C₄ alkyl;

L² is -CH₂-, -CH(CH₃)-, or -CH(OH)-;

ring A is a substituted or unsubstituted 5-membered monocyclic Ci-C₄heteroarylene

containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with R¹⁴;

L⁴ is -CH₂- or -CH(CH₃)-;

p is 0 or 1.

The topical formulation of claim 13, wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or Ci-C₄alkyl;

R^E is C C₄alkyl;

L² is -NH-, -CH₂-, -CH(CH₃)-, -CH(OH)-, -NHCH₂- or -NHCH(CH₃)-;

ring A is a substituted or unsubstituted 6-membered monocyclic C Csheteroarylene

containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with

R¹⁴;

L⁴ is absent, -CH₂-, or -CH(CH₃)-;

p is 0 or 1.

The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of a dermal fibrotic disease or condition.

The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of scleroderma, Raynaud's phenomenon, calcinosis, scarring, Dupuytren's disease; cutaneous irradiation syndrome; capsular contracture; retroperitoneal fibrosis; or a combination thereof. The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of cutaneous scleroderma or systemic scleroderma.

The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of skin fibrosis, cutaneous scleroderma, systemic sclerosis, Raynaud's phenomenon, keloids, recurrence of keloids post resection, hypertrophic scars, revision of scars, scars post-burns, Dupuytrens disease, cutaneous irradiation syndrome, capsular contracture, or fibrosis post ligament and orthopedic surgery.

The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of atopic dermatitis, bullous disorder, collagenoses, psoriasis, psoriatic lesions, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, keloid scar formation, scleroderma, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma or melanoma

The topical formulation of any one of claims 1-15, wherein the topical formulation comprises an LPAl receptor antagonist in an amount effective for the treatment of scarring, a proliferative disease or condition, a fibrotic disease or condition or an inflammatory disease or condition.

A method of treating a dermal disease or condition in a mammal, comprising administering to the mammal in need thereof a therapeutically-effective amount of an LPAl receptor antagonist.

The method of claim 22, wherein the dermal disease or condition is a dermal fibrotic disease or condition.

The method of claim 22, wherein the dermal disease or condition is scleroderma, Raynaud's phenomenon, calcinosis, scarring, Dupuytren's disease; cutaneous irradiation syndrome; capsular contracture; retroperitoneal fibrosis; or a combination thereof.

The method of claim 22, wherein the dermal disease or condition is cutaneous scleroderma or systemic scleroderma.

The method of claim 22, wherein the dermal disease or condition is skin fibrosis, cutaneous scleroderma, systemic sclerosis, Raynaud's phenomenon, keloids, recurrence of keloids post resection, hypertrophic scars, revision of scars, scars post-burns, Dupuytrens disease, cutaneous irradiation syndrome, capsular contracture, or fibrosis post ligament and orthopedic surgery.

27. The method of claim 22, wherein the dermal disease or condition is atopic dermatitis, bullous disorder, collagenoses, psoriasis, psoriatic lesions, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, keloid scar formation, scleroderma, Folliculitis keloidalis nuchae, Kawasaki Disease, Sjogren-Larsso Syndrome, Grover's disease, acne, a first degree burn, a second degree burn, a third degree burn, a fourth degree burn, solar keratosis, squamous cell carcinoma or melanoma

28. The method of claim 22, wherein the dermal disease or condition is scarring, a proliferative disease or condition, a fibrotic disease or condition or an inflammatory disease or condition.

29. The method of any one of claims 22-28, wherein the LPA1 receptor antagonist is a

compound having the structure of Formula (I)

Formula (I)

wherein,

L¹ is Ci-C₄alkylene or C₃-C₆cycloalkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃;

R⁸ is H or -CH₃;

CY is Ci-Cealkyl, substituted or unsubstituted C₃-C6Cycloalkyl, or substituted or

unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c each R^c is independently F, CI, Br, I, -OH, -CN, C C₄alkyl, C C₄fluoroalkyl, C C₄fluoroalkoxy, or Ci-C₄alkoxy;

The method of claim 29, wherein the compound of Formula (I) has the following structure:

31. The method of claim 29, wherein the compound of Formula (I) has the structure of Formula

(II):

Formula (II)

wherein,

n is 0, 1, or 2.

32. The method of any one of claims 29-31 , wherein:

L¹ is -CH₂-, or cyclopropyl-l ,l-diyl;

R³ is H or -CH₃;

R⁸ is -CH₃.

33. The method of claim 29, wherein the LPAl receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 22-28, wherein the LPAl receptor antagonist has structure of Formula (III):

Formula (III)

wherein

L¹ is absent, or a Ci-Cealkylene;

R³ is H, -CH₃, -CH₂CH₃, or -CF₃;

R⁴ is -NHC(=0)OCH(R⁸)-CY;

R⁸ is H, or -CH₃;

CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R^c; each R^c is independently F, CI, Br, I, -OH, -CN, C_r C4alk l, Ci-C4fhioroalkyl, Ci-C4fiuoroalkoxy, or Ci-C4alkoxy;

or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein:

R¹ is -C0₂H or -C0₂R^D;

R³ is H or -CH₃; 36. The method of claim 34, wherein the LPAl receptor antagonist is 6-(4-{4-[l-(2-Chloro- phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hex-5-ynoic acid, or 7-(4- {4-[l-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hept-6- ynoic acid, or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 22-28, wherein the LPAl receptor antagonist has the structure of Formula (VI):

Formula (VI)

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, or tetrazolyl;

R^D is H or Ci-C₆alkyl;

R^E is Ci-C₆alkyl, C₃-C₆cycloalkyl, or substituted or unsubstituted phenyl; L³ is a substituted or unsubstituted C₃-C₆alkylene, a substituted or unsubstituted C₃-

Cgfluoroalkylene, or a substituted or unsubstituted C3-Csheteroalkylene, where if L³ is substituted then L³ is substituted with 1, 2 or 3 R¹³; each R¹³ is independently F, d- C₄alkyl, Ci-C₄fluoroalkyl, or -OH;

each R^c is independently halogen, -CN, -N0₂, -OH, Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci- C₄fluoroalkoxy, Ci-C₄alkoxy, or d-Qheteroalkyl;

R³ is H or C C₄alkyl;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

The method of claim 37, wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or Ci-C₄alkyl;

R^E is Ci-C₄alkyl;

L³ is a substituted or unsubstituted C3-C₄alkylene, a substituted or unsubstituted C3-

C₄fluoroalkylene, or a substituted or unsubstituted C₃-C₆heteroalkylene; where if L³ is substituted then L³ is substituted with 1, 2 or 3 R¹³; each R¹³ is independently selected from F, -CH₃, -CH₂CH₃, -CF₃, and -OH;

R³ is -H, -CH₃ or -CH₂CH₃.

The method of any one of claims 22-28, wherein the LPAl receptor antagonist has the structure of Formula (VII)

Formula (VII)

wherein,

R¹ is -C0₂R^D, -C(=0)NHS0₂R^E, -C(=0)N(R^D)₂, -CN, or tetrazolyl;

R^Dis H or C C₆ alkyl;

R^E is C1-C6 alkyl or a substituted or unsubstituted phenyl;

L² is absent, -C(=0)-, -N(R^D)-, substituted or unsubstituted C C₄ alkylene, or substituted or unsubstituted Ci-C₄ heteroalkylene, where if L² is substituted, then L² is substituted with R¹², where R¹² is F, Ci-C₄alkyl, -OH, or -0R^D;

CrC₅heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R , each R is independently selected from halogen, -CN, -OH, Ci-C₄alkyl, C C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl;

L⁴ is absent, or a substituted or unsubstituted CpQ alkylene, where if L⁴ is substituted then L⁴ is substituted with R¹³, where R¹³ is F, C C₄alkyl, -OH, or -OR^D;

R³ is H or Ci-C₄ alkyl;

CrQfluoroalkoxy, Ci-C₄alkoxy, and Ci-C₄heteroalkyl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The method of claim 39, wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or Ci-C₄ alkyl;

R^E is Ci-C₄ alkyl;

L² is -CH₂-, -CH(CH₃)-, or -CH(OH)-;

L⁴ is -CH₂- or -CH(CH₃)-;

p is 0 or 1.

The method of claim 39, wherein:

R¹ is -C0₂R^D, or -C(=0)NHS0₂R^E;

R^D is H or Ci-C₄alkyl;

R^E is Ci-C₄alkyl;

L² is -NH-, -CH₂-, -CH(CH₃)-, -CH(OH)-, -NHCH₂- or -NHCH(CH₃)-;

ring A is a substituted or unsubstituted 6-membered monocyclic C₃-C5heteroarylene

R¹⁴;

L⁴ is absent, -CH₂-, or -CH(CH₃)-;

p is 0 or 1.

The method of any one of claims 22-41 , wherein the LPAl antagonist is topically administered, orally administered, or parenterally administered to the mammal.

The method of any one of claims 22-41 , wherein the LPAl receptor antagonist is systemically administered to the mammal.

The method of any one of claims 22-41 , wherein the LPAl receptor antagonist is orally administered to the mammal.

45. The method of claim 44, wherein the LPAl receptor antagonist is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.

46. The method of any one of claims 22-41 , wherein the LPAl receptor antagonist is

administered to the mammal by injection or intraveneously.

47. The method of any one of claims 22-41 , wherein the LPAl receptor antagonist is topically administered to the mammal.

48. The method of claim 47, wherein the LPAl receptor antagonist is topically administered to the mammal in the form of an ointment, cream, lotion, paste, gel, stick, a film, spray, a patch or wound dressing.