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WO2025061764A1 - Traitement de ciliopathies et de dysfonctionnements ciliaires - Google Patents

Traitement de ciliopathies et de dysfonctionnements ciliaires Download PDF

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Publication number
WO2025061764A1
WO2025061764A1 PCT/EP2024/076112 EP2024076112W WO2025061764A1 WO 2025061764 A1 WO2025061764 A1 WO 2025061764A1 EP 2024076112 W EP2024076112 W EP 2024076112W WO 2025061764 A1 WO2025061764 A1 WO 2025061764A1
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WIPO (PCT)
Prior art keywords
syndrome
compound
ciliopathy
dysplasia
dysfunction
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PCT/EP2024/076112
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English (en)
Inventor
Luis BRISENO-ROA
Anita RAYAR
Paul DUPUYDS
France DE MALGLAIVE
Iris BARNY
Jean-Michel Rozet
Jean-Philippe Annereau
Sophie SAUNIER
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Medetia
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Fondation Imagine
Universite Paris Cite
Original Assignee
Medetia
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Fondation Imagine
Universite Paris Cite
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Publication of WO2025061764A1 publication Critical patent/WO2025061764A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the treatment of ciliopathies and manifestations of ciliopathies, using 2-(3-(3',4-difhioro-[l,r-biphenyl]-3-ylcarboxamido)phenoxy) acetic acid or a pharmaceutically acceptable salt and/or solvate thereof.
  • Ciliopathies are a group of diseases characterized by cilia dysfunction that affect the cellular cilia and/or the cilia anchoring structures, and that result in abnormal formation and/or function of cilia. Ciliopathies can have different causes, including genetic, senescent, traumatic, infectious, and idiopathic.
  • Cilia are a component of most types of cells in the animal body. There are two major classes of cilia: motile and non-motile cilia. Most non-motile cilia are termed primary cilia and serve as sensory organelles. Primary cilia are important in guiding embryonic development and in adult physiology.
  • abnormalities in the formation and function of cilia can result in a set of malformations while an embryo is developing, and in a collection of features including, but not limited to, retinal degeneration, renal diseases, cerebral abnormalities, skeletal defects, and combinations thereof.
  • ciliopathies include acrocallosal syndrome, Al-Gazali-Bakalinova syndrome, Alstrbm syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex-Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early- onset severe retinal dystrophy (EOSRD), Ellis-van Creveld syndrome, Greig cephalopolysyndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity and spermat
  • a method of treating ciliopathy-associated diseases including administering a compound that targets at least one G-protein coupled receptor, such as agonists of EP2 (also known as prostaglandin E2 receptor 2 or prostaglandin E2 receptor EP2 subtype), for example alprostadil (prostaglandin El or PGE1) or taprenepag (CP-544326).
  • EP2 also known as prostaglandin E2 receptor 2 or prostaglandin E2 receptor EP2 subtype
  • alprostadil prostaglandin El or PGE1
  • taprenepag CP-544326
  • the present invention is thus directed to compound 1 or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment of ciliopathies.
  • This invention thus relates to a compound for use in the treatment of a ciliopathy in a subject in need thereof, wherein the compound is 2-(3-(3',4-difluoro-[ 1,1 '-biphenyl]- 3-ylcarboxamido)phenoxy)acetic acid or a pharmaceutically acceptable salt and/or solvate thereof.
  • the ciliopathy is genetic, senescent, traumatic, infectious or idiopathic.
  • the ciliopathy is selected from acrocallosal syndrome, Al- Gazali-Bakalinova syndrome, Alstrbm syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocer
  • the invention relates to a compound for use in the treatment of a ciliopathy in a subject in need thereof, wherein the compound is 2-(3-(3',4-difluoro- [l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid or a pharmaceutically acceptable salt and/or solvate thereof, wherein the the ciliopathy is genetic, senescent, traumatic, or idiopathic.
  • the ciliopathy is selected from acrocallosal syndrome, Al- Gazali-Bakalinova syndrome, Alstrbm syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity and spermat
  • the ciliopathy results from the deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: ACOT13, ACP5, ACTRT1, ADAMTS9, AHI1, AIPL1, ALG5, ALG9, ALMS1, ANKS6, ARL3, ARL6, ARL13B, ARMC9, B9D1, B9D2, BBIP1, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, C2CD3, C8or/37, CBY1, CC2D1A, CC2D2A, CCNQ, CENPF, CEP19, CEP41, CEP55, CEP83, CEP104, CEP120, CEP164, CFAP410, CPLANE1, CRB1, CSPP1, CYS1, DCDC2, DDX59, DHCR7, DNAH5, DNAH11, DNAI1, DNAI2.
  • the ciliopathy results from the deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: NPHP1 and NPHP6.
  • the ciliopathy is selected from osteoarthritis, early onset osteoarthritis, osteoporosis, bone fragility, bone demineralization, degenerative disc disease, osteophytes formation, juvenile idiopathic arthritis, skeletal dysplasia, osteochondritis dissecans, achondroplasia, hypochondroplasia, and progeria.
  • the ciliopathy is selected from ciliopathies induced by microgravity, and ionizing radiation-induced cellular senescence.
  • the ciliopathy is characterized by visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, or their combinations.
  • the invention also provides a compound for use in the treatment of a manifestation of ciliopathies selected from visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, and combinations thereof, in a subject suffering from a ciliopathy, wherein the compound is 2-(3-(3',4-difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid or a pharmaceutically acceptable salt and/or solvate thereof.
  • ciliopathies selected from visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, and combinations thereof, in a subject suffering from a ciliopathy, wherein the compound is 2-(3-(3',4-difluoro-[l,l
  • the invention further provides a compound for use in a method for preserving or improving ciliary function in a subject in need thereof, optionally a subject suffering from a ciliopathy, wherein the compound is 2-(3-(3',4-difluoro-[l,l'-biphenyl]-3- ylcarboxamido)phenoxy)acetic acid or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound is to be administered orally, topically or parenterally. In one embodiment, wherein the compound is to be administered orally. In another embodiment, the compound is to be administered topically, preferably under the form of eye drops.
  • a and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the expressions “at least one” and “one or more” are interchangeable.
  • administering refers to a means of providing an agent or a composition containing the agent to a subject in need thereof in a manner that results in the agent being inside the subject’s body.
  • Such an administration can be by any route including, without limitation, oral, injection (e.g., subcutaneous, intravenous, parenterally, intraperitoneally, into the CNS), transdermal (e.g., vagina, rectum, oral mucosa), or inhalation (e.g., oral or nasal).
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • “Pharmaceutically acceptable” means that the component is not deleterious to the subject to which it is administered and is compatible with any other component administered together.
  • “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical excipients or carriers, especially excipients or carriers that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, preferably a human. This includes any and all solvents, dispersion media, carriers such as a phosphate buffered saline solution, water, and emulsions such as an oil/water or water/oil emulsion, and various types of stabilizers, preservatives, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents and other similar ingredients.
  • “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • Solvate refers to a molecular complex comprising a compound and contains stoichiometric or sub- stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol.
  • solvent molecule such as ethanol.
  • hydrate refers to when said solvent is water.
  • Subject refers to a mammal, preferably a human.
  • a subject is a mammal, preferably a human, suffering from the targeted disease and/or prone to develop the targeted disease.
  • the subject is a “patient”, i.e., a mammal, preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure or is monitored for the development of the targeted disease.
  • “Suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease.
  • the term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease.
  • a patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • a patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
  • “Therapeutically effective amount” or “effective amount” refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages.
  • Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific doses of the compound as disclosed herein for any particular subject depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a ciliopathy ex vivo, in vitro or in vivo.
  • Treatment refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and/or slow down (lessen) one or more of the symptoms or manifestations of a disease, in a subject in need thereof.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • a subject or mammal is successfully “treated” for a disease if, after receiving a therapeutic amount of the compound as disclosed herein, the subject or mammal shows, (1) delayed or prevented onset of the disease; (2) slowed down or stopped progression, aggravation, or deterioration of one or more symptoms of the disease; (3) ameliorations of one or more symptoms of the disease; (4) reduction of the severity or incidence of the disease; or (5) curing the disease.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • “treating” or “treatment” refers to a therapeutic treatment.
  • “treating” or “treatment” refers to a prophylactic or preventive treatment.
  • “treating” or “treatment” refers to both a prophylactic (or preventive) treatment and a therapeutic treatment.
  • This invention thus relates to a compound for use in the treatment of ciliopathies.
  • the invention relates to compound 1 or pharmaceutically acceptable salts and/or solvates thereof.
  • Compound 1 is 2-(3-(3',4-difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy) acetic acid, also known as PGN-9856, and has the following structure:
  • compositions of compound 1 include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compound may also form internal salts, it is also within the scope of the invention.
  • compositions may be prepared by one or more of these methods:
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • Compound 1 is commercially available and methods for preparing the same are known in the art. Medical indications
  • Compound 1, pharmaceutically acceptable salts and/or solvates thereof, and pharmaceutical compositions containing the same, described herein are useful in the treatment of ciliopathies in a subject in need thereof.
  • subjects to be treated according to the methods described herein include mammals and preferably humans.
  • the mammal is a human patient.
  • the present invention provides a compound for use in the treatment of a ciliopathy in a subject in need thereof, wherein the compound is 2-(3-(3',4- difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid (compound 1) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a method for treating a ciliopathy in a subject in need thereof comprising administering to the subject an effective amount of 2-(3-(3',4- difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid (compound 1) or a pharmaceutically acceptable salt and/or solvate thereof.
  • the ciliopathy results from the deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: AHI1, AEMS1, ARE6, ARL13B, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, CC2D2A, DNAH5, DNAH11, DNAI1, DNAI2, DYNC2H1, EVC, EVC2, GLIS2, GUCY2D, IFT88, IFT122, INPP5E, INVS, IQCB1, KTU, LRRC50, MKKS, MKS1, NPHP1, NPHP3, NPHP4, NPHP5, NPHP6, 0FD1, PKD1, PKD2, PKHD1, RPE65, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TMEM67, TMEM216, TRIM32, TTC8, and TXNDC3.
  • genes AHI1, AEMS1, ARE6, ARL13B,
  • Deletions, mutations and loss of functions causing genetic ciliopathies can be biallelic or monoallelic.
  • biaselic it is meant that the deletions, mutations and loss of functions are present in/affect both alleles of the gene(s), with the deletions, mutations and loss of functions on each allele being either identical or different.
  • diallelic it is meant that the deletions, mutations and loss of functions are present in/affect only one allele of the gene(s).
  • the ciliopathy results from the deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: NPHP1 and NPHP6.
  • the ciliopathy results from one or more mutation in one or more of the following genes: ACOT13, ACP5, ACTRT1, ADAMTS9, AHI1, AIPL1, ALG5, ALG9, ALMS1, ANKS6, ARL3, ARL6, ARL13B, ARMC9, B9D1, B9D2, BBIP1, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, C2CD3, C8or/37, CBY1, CC2D1A, CC2D2A, CCNQ, CENPF, CEP19, CEP41, CEP55, CEP83, CEP104, CEP120, CEP164, CFAP410, CPLANE1, CRB1, CSPP1, CYS1, DCDC2, DDX59, DHCR7, DNAH5, DNAH11, DNAI1, DNAI2, DNAJB11, DYNC2H1, DYNC2I1, DYNC2
  • the ciliopathy results from one or more mutation in one or more of the following genes: AHI1, ALMS1, ARE6, ARE13B, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, CC2D2A, DNAH5, DNAH11, DNAI1, DNAI2, DYNC2H1, EVC, EVC2, GLIS2, GUCY2D, IFT88, IFT122, INPP5E, INVS, IQCBI, KTU, LRRC50, MKKS, MKS1, NPHP1, NPHP3, NPHP4, NPHP5, NPHP6, OFD1, PKD1, PKD2, PKHD1, RPE65, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TMEM67, TMEM216, TRIM32, TTC8, and TXNDC3.
  • the ciliopathy results from one or more mutation in one or more of the following genes: NPHP
  • the ciliopathy results from a loss of function of one or more of the following genes: AHI 1, ALMS 1, ARL6, ARL13B, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBSIO, BBSI2, BRCC3, CC2D2A, DNAH5, DNAHII, DNAII, DNAI2, DYNC2HI, EVC, EVC2, GLIS2, GUCY2D, IFT88, IFT122, INPP5E, INVS, IQCBI, KTU, LRRC50, MKKS, MKS1, NPHP1, NPHP3, NPHP4, NPHP5, NPHP6, 0FD1, PKD1, PKD2, PKHD1, RPE65, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TMEM67, TMEM216, TRIM32, TTC8, and TXNDC3.
  • the ciliopathy results from a loss of function of one or more of the following genes: AHI 1, AL
  • the ciliopathy results from a deletion of one or more of the following genes: ACOTI3, ACP5, ACTRTI, ADAMTS9, AHII, AIPLI, ALG5, ALG9, ALMS1, ANKS6, ARL3, ARL6, ARL13B, ARMC9, B9DI, B9D2, BBIPI, BBSI, BBS2, BBS4, BBS5, BBS7, BBS9, BBSIO, BBSI2, BRCC3, C2CD3, C8or/37, CBYI, CC2DIA, CC2D2A, CCNQ, CENPF, CEP19, CEP41, CEP55, CEP83, CEP104, CEP120, CEP164, CFAP410, CPLANE1, CRB1, CSPP1, CYSI, DCDC2, DDX59, DHCR7, DNAH5, DNAHII, DNAII, DNAI2, DNAJBII, DYNC2HI, DYNC2I
  • the ciliopathy results from a deletion of one or more of the following genes: AHI1, ALMS1, ARL6, ARL13B, BBSI, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS 12, BRCC3, CC2D2A, DNAH5, DNAH11, DNAI1, DNAI2, DYNC2H1, EVC, EVC2, GLIS2, GUCY2D, IFT88, IFT122, INPP5E, INVS, IQCB1, KTU, LRRC50, MKKS, MKS1, NPHP1, NPHP3, NPHP4, NPHP5, NPHP6, 0FD1, PKD1, PKD2, PKHD1, RPE65, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TMEM67, TMEM216, TRIM32, TTC8, and TXNDC3.
  • the ciliopathy results from a deletion of one or more of the following genes: NPHP1
  • Examples of genetic ciliopathies include acrocallosal syndrome, Al-Gazali- Bakalinova syndrome, Alstrom syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity and spermatogenic failure
  • the ciliopathy is selected from acrocallosal syndrome, Al- Gazali-Bakalinova syndrome, Alstrom syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity and sper
  • a “senescent ciliopathy” refers to a ciliopathy caused by senescence. Especially, a senescent ciliopathy may result from cellular aging and aging process.
  • the ciliopathy is a senescent ciliopathy.
  • senescent ciliopathies include diseases related to cartilage and bone, including osteoarthritis, early onset osteoarthritis, osteoporosis, bone fragility, bone demineralization, degenerative disc disease, osteophytes formation, juvenile idiopathic arthritis, skeletal dysplasia, osteochondritis dissecans, achondroplasia, hypochondroplasia, and progeria.
  • the ciliopathy is selected from osteoarthritis, early onset osteoarthritis, osteoporosis, bone fragility, bone demineralization, degenerative disc disease, osteophytes formation, juvenile idiopathic arthritis, skeletal dysplasia, osteochondritis dissecans, achondroplasia, hypochondroplasia, and progeria.
  • a “traumatic ciliopathy” refers to a ciliopathy having a traumatic cause. Especially, a traumatic ciliopathy may result from exposition to microgravity or to sources of radiations.
  • the ciliopathy is a traumatic ciliopathy.
  • Examples of traumatic ciliopathies include ciliopathies induced by microgravity, and ionizing radiation (IR)-induced cellular senescence.
  • the ciliopathy is selected from ciliopathies induced by microgravity, and ionizing radiation (IR)-induced cellular senescence.
  • An “infectious ciliopathy” refers to a ciliopathy caused by an infection.
  • an infectious ciliopathy may result from infections by bacteria or viruses, for example an infection by a coronavirus such as SARS-CoV-2 (COVID- 19), SARS-CoV- 1, influenza virus, or rhino virus I.
  • the ciliopathy is an infectious ciliopathy.
  • infectious ciliopathies include ciliopathies caused by an infectious agent, especially by a bacteria or by a virus such as SARS-CoV-2, SARS-CoV-1, influenza virus, or rhinovirus I.
  • the ciliopathy is selected from ciliopathies caused by an infectious agent, especially by a bacteria or by a virus such as SARS-CoV-2, SARS-CoV-1, influenza virus, or rhinovirus I.
  • the ciliopathy is not an infectious ciliopathy.
  • an “idiopathic ciliopathy” herein refers to a ciliopathy having apparently no genetic, senescent, traumatic and/or infectious cause.
  • the ciliopathy is an idiopathic ciliopathy.
  • the ciliopathy is selected from acrocallosal syndrome, Al- Gazali-Bakalinova syndrome, Alstrbm syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity
  • the ciliopathy is selected from acrocallosal syndrome, Al- Gazali-Bakalinova syndrome, Alstrbm syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Bazex- Dupre-Christol syndrome, bilateral polycystic kidney disease, biliary renal neurologic and skeletal syndrome, COACH syndrome, Caroli disease, Carpenter syndrome, complex lethal osteochondrodysplasia, cranioectodermal dysplasia, early-onset severe retinal dystrophy (EOSRD), Ellis- van Creveld syndrome, Greig cephalopoly syndactyly syndrome, hydrolethalus syndrome, infantile polycystic kidney disease, Joubert syndrome, Kallmann syndrome, Leber congenital amaurosis, Lowe oculocerebrorenal syndrome, McKusick-Kaufman syndrome, Meckel-Gruber syndrome, morbid obesity
  • the ciliopathy is characterized by visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, or any combinations thereof.
  • a “visual dysfunction” includes retinitis pigmentosa, maculopathy, retinal dystrophy, photophobia, hyperopia, keratoconus, blindness (at birth or developing during infancy or later during adulthood) and/or retinal defects, such as retinal degenerationoptometric, retinogram alterations abnormalities, optometric and/or retinogram alterations.
  • Retinitis pigmentosa, maculopathy and retinal dystrophy may be assessed for example by the presence of coarse nystagmus, sluggish or near-absent pupillary responses.
  • kidney dysfunction for example comprises cystic kidney or kidney fibrosis, dilatation of the renal collecting ducts, renal insufficiency, bilateral renal enlargement with microcystic dilatation, glomerulosclerosis cystic renal dystrophy, renal dysplasia, nephronophthisis and/or focal segmental glomerulosclerosis.
  • liver dysfunction for example comprises hepatic fibrosis, intrahepatic biliary dysgenesis, non-obstructive dilation of the intrahepatic bile ducts in the liver and/or fibrocystic disease (for example biliary dysgenesis that includes congenital hepatic fibrosis, bile duct dilatation and cyst formation).
  • olfactory dysfunction for example comprises anosmia, hyposmia and/or parosmia.
  • An “intellectual deficiency” could be associated with agenesis of the corpus callosum, clinical features comprising for example learning abilities dysfunctions, mental retardation, deficits in "higher” language function, complex information processing abilities, complex attention and/or memory skills, subtle social differences, cognitive difficulties and/or development delay.
  • Electrode it is herein meant a syndrome wherein at least one function and/or structure of the brain is altered, such as hypoplasia of the corpus callosum, cerebellar hypoplasia, delayed myelination and/or progressive parenchymal volume loss.
  • the expression “cardiac malformation” for example comprises failure of the ductus arteriosus, a blood vessel that bypasses the lungs in fetal development, to close after birth (Patent Ductus Arteriosus), a hole in the septum that separates the ventricles of the heart (Atrial & Ventricular Septal Defects), ventricular hypertrophy, and an overriding aorta (Tetralogy of Fallot).
  • cardiac dysfunction for example comprises hypertension, arrhythmia, mitral valve prolapse or aortic stenosis, myocardial infarction, atherosclerosis, pericarditis, endocarditis, and cardiomyopathy.
  • the compound as disclosed herein is effective for use in preserving or improving cilial function in the hypothalamus, retina and/or olfactory epithelium, e.g., preserving or improving function (e.g., motility) of cilia and/or preserving or improving quantity or density of functioning cilia.
  • the compound as disclosed herein is also effective to preserve or improve the composition of the elements of cilia, such as the protein content of cilia.
  • the present invention provides a compound for use in the treatment of a manifestation of ciliopathies selected from visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, and combinations thereof, in a subject suffering from a ciliopathy, wherein the compound is 2-(3-(3',4-difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid (compound 1) or a pharmaceutically acceptable salt and/or solvate thereof.
  • ciliopathies selected from visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, and combinations thereof, in a subject suffering from a ciliopathy, wherein the compound is 2-(3-(3',4-difluoro-
  • compositions for preserving or improving ciliary function in a subject in need thereof, optionally a subject suffering from a ciliopathy said pharmaceutical composition comprising 2-(3-(3',4-difluoro-[l J'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid (compound 1) or a pharmaceutically acceptable salt and/or solvate thereof and optionally at least one pharmaceutically acceptable excipient.
  • the subject is a human.
  • the subject is a male. In one embodiment, the subject is a female.
  • the subject is an adult.
  • the subject is a pediatric patient; e.g., of an age from 0 to 18 years old, e.g., from 1 to 15 years old, or from 1 to 5 years old, or from 5 to 10 years old, or from 10 to 15 years old.
  • the subject is a fetus.
  • the compound is to be administered in utero.
  • the compound is to be administered to a pregnant woman when her fetus has been prenatally diagnosed with a ciliopathy. Indeed, it is expected that the compound may be able to cross the placental barrier and reach the fetus.
  • the subject is diagnosed with a ciliopathy.
  • the subject is diagnosed with a ciliopathy and suffers from a manifestation of ciliopathies selected from visual dysfunction, kidney dysfunction, liver dysfunction, olfactory dysfunction, skeletal dysplasia, ataxia, intellectual deficiency, male infertility, encephalopathy, cardiac malformation, cardiac dysfunction, and combinations thereof.
  • Diseases and disorders such as ciliopathies are often associated with one or more genetic mutations.
  • the subject is diagnosed with having a ciliopathy and is also diagnosed to have a particular genetic mutation, for example, one that is known to be a cause of the ciliopathy in question, although it often cannot be proven that a particular patient’s disease or disorder is caused by the particular mutation that a person has been diagnosed with having.
  • diagnosis to have a particular genetic mutation means that a subject or patient has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and found to have the mutation in question.
  • the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: ACOT13, ACP5, ACTRT1, ADAMTS9, AHI1, AIPL1, ALG5, ALG9, ALMS1, ANKS6, ARL3, ARL6, ARL13B, ARMC9, B9D1, B9D2, BBIP1, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, C2CD3, C8or/37, CBY1, CC2D1A, CC2D2A, CCNQ, CENPF, CEP19, CEP41, CEP55, CEP83, CEP104, CEP120, CEP164, CFAP410, CPLANE1, CRB1, CSPP1, CYS1, DCDC2, DDX59, DHCR7, DNAH5, DNAH11, DNAI1, DNAI2.
  • the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: AHI1, AEMS1, ARE6, ARL13B, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BRCC3, CC2D2A, DNAH5, DNAH11, DNAI1, DNAI2, DYNC2H1, EVC, EVC2, GLIS2, GUCY2D, IFT88, IFT122, INPP5E, INVS, IQCB1, KTU, LRRC50, MKKS, MKS1, NPHP1, NPHP3, NPHP4, NPHP5, NPHP6, OFD1, PKD1, PKD2, PKHD1, RPE65, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TMEM67, TMEM216, TRIM32, TTC8, and TXNDC3.
  • genes AHI1, AEMS1, ARE6, ARL13B, B
  • the subject carries a biallelic deletion, mutation, or loss of function.
  • a biallelic deletion, mutation, or loss of function it is meant that the subject carries a deletion, mutation, or loss of function in/of both alleles of the gene(s), with the deletions, mutations, or loss of functions on each allele being either identical or different.
  • the subject carries a monoallelic deletion, mutation, or loss of function.
  • a monoallelic deletion, mutation, or loss of function it is meant that the subject carries a deletion, mutation, or loss of function in/of only one allele of the gene(s).
  • the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: NPHP1 and NPHP6.
  • the uses of the invention may be beneficial for subjects who have been diagnosed with a ciliopathy but are not yet experiencing the typical symptoms associated with the disease state. Uses of the invention may also be beneficial for subjects who are at risk of developing a ciliopathy due to, for example, a mutation in the subject or the subject’s family lineage known to cause a ciliopathy.
  • the subject has been diagnosed as being at risk of developing said ciliopathy, and compound 1 as described herein prevents or delays the onset and/or development of the ciliopathy in the subject.
  • the subject has been diagnosed as being at risk of developing said ciliopathy by virtue of having a mutation in a gene as described herein.
  • the compound is preferably administered within a pharmaceutical composition.
  • the pharmaceutical composition comprises 2-(3-(3',4- difluoro-[l,l'-biphenyl]-3-ylcarboxamido)phenoxy)acetic acid (compound 1), or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).
  • Pharmaceutical compositions may be prepared by conventional means known in the art including, for example, mixing compound 1 as described herein, or a pharmaceutically acceptable salt and/or solvate thereof, with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition or dosage form is formulated to provide, when administered, an amount of the compound of interest sufficient to treat a ciliopathy or a manifestation of ciliopathies.
  • the compound is to be administered by systemic administration, e.g., via a parenteral or a non-parenteral route.
  • the route of administration is oral (enteral).
  • the route of administration is parenteral, e.g., by injection, such as by intravenous, intramuscular, intrathecal or subcutaneous injection.
  • the compound is to be administered by local administration, e.g., by topical administration.
  • compound 1, or a pharmaceutically acceptable salt and/or solvate thereof is to be administered orally.
  • the dosage form comprising the compound or the pharmaceutical composition comprising the compound can be an oral dosage form, a parenteral dosage form, a topical or rectal dosage form, an intranasal dosage form.
  • the dosage form is an oral dosage form.
  • the oral dosage form is for example a pill, capsule, caplet, tablet, dragee, powder, granule, film, lozenge or liquid.
  • the dosage form can be a topical dosage form including eye drops.
  • the compound is to be administered as the sole active agent.
  • a second pharmaceutically active agent can be concurrently administered.
  • the second active agent is capable of treating a ciliopathy.
  • the second active agent can be administered in the same pharmaceutical composition or dosage form as the compound as disclosed herein.
  • the second active agent can be administered in a different pharmaceutical composition or dosage form.
  • the agents and compositions described herein are to be administered in an effective amount or quantity sufficient to treat or prevent a ciliopathy in a subject.
  • the dose can be adjusted within this range based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. Determination of an effective amount is well within the capability of those skilled in the art.
  • an appropriate dosage level will generally be about 0.01 to 250 mg per kg patient body weight per day (mg/kg per day) which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 100 mg/kg per day, such as ranging from 0.1 to 50 mg/kg per day.
  • the compositions are preferably provided in dosage forms containing 1.0 to 1000 mg of the active ingredient.
  • the compound may be administered as a single daily dose, divided over one or more daily doses, for example on a regimen of 1 to 4 times per day.
  • Figure 1 is a histogram showing the EP2 agonist activity of the tested compounds expressed as a percentage of the EP2 agonist activity of standard reference agonist PGE2 (example 1).
  • Figure 2 is a graph showing the fraction of ciliated cells for primary fibroblasts with NPHP6 loss-of-functions in presence of DMSO (control) or of the EP2 agonists taprenepag or compound 1 (example 2).
  • Figure 3 is a graph showing the fluorescence intensity of the cilia of primary fibroblasts with NPHP6 loss-of-functions in presence of DMSO (control) or of the EP2 agonists taprenepag or compound 1 (example 2).
  • Figure 4 is a graph showing the fraction of ciliated cells for patient-derived urine epithelial cells with NPHP1 loss-of-functions in the presence of DMSO (control) or of the EP2 agonists taprenepag or compound 1 (example 3).
  • Figure 5 is a graph showing the evolution of the percentage of remaining compound overtime once exposed to mice liver microsomes (example 4).
  • Compound 1 as disclosed herein 2-(3-(3',4-difluoro-[l,T-biphenyl]-3- ylcarboxamido)phenoxy) acetic acid; reference EP2 agonists: taprenepag, omidenepag, and evatanepag; negative control: taprenepag isopropyl.
  • the CHO (Chinese hamster ovary) cells expressing human EP2 receptor (also known as prostaglandin E2 receptor 2 or prostaglandin E2 receptor EP2 subtype) were suspended in HBSS buffer supplemented with 20 mM HEPES (pH 7.4) and 500 pM IBMX, and then distributed in microplates at a density of 10 4 cells/well. Following a 30-minute incubation at 37 °C, the cells were exposed to the tested compounds, with separate assay wells containing 10 pM PGE2 (also known as prostaglandin E2) for stimulated control measurements. The compounds were tested at 1.0E-07 M (0.1 pM).
  • cAMP production was measured using the HTRF detection method: after the incubation period, the cells were lysed, and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) were added. Following a 60-minute incubation at room temperature, the fluorescence transfer was measured using a microplate reader at excitation wavelength (Xex) of 337 nm and emission wavelengths (Xem) of 620 nm and 665 nm. The cAMP concentration was determined by calculating the ratio of the signal measured at 665 nm to that measured at 620 nm. The results were expressed as a percentage of the control response to 10 pM PGE2. The standard reference agonist, PGE2, was included in each experiment at various concentrations to generate a concentration-response curve and calculate its EC50 value.
  • Taprenepag demonstrated an activation response of approximately 80% of that of control. Both omidenepag and evatanepag exhibited slightly lower activation levels, ranging from 60% to 70%. Notably, compound 1 demonstrated an activation response surpassing that of PGE2 (control), reaching approximately 120% of its activity.
  • a negative control was included using the prodrug of taprenepag (taprenepag isopropyl), which is well-established to lack receptor activation.
  • fibroblasts were derived from skin biopsies from patients with a LOF mutation in the NPHP6 gene (also known as CEP290). Fibroblasts were isolated by selective trypsinization and proliferated at 37°C with 5% CO2 in “complete medium” supplemented with 10% FBS (fetal bovine serum - Life Technologies). Cells were grown in 75 cm 2 flasks and seeded on glass bottom 96-wells plates. Ciliogenesis was induced by incubation in serum-free medium for 48h; after first 24h of serum starvation, cells were incubated 24h with either taprenepag or compound 1 at final concentration of 1 pM and 0.04% DMSO.
  • FBS fetal bovine serum - Life Technologies
  • the changes in fluorescence intensity of the cilia are reported in Figure 3.
  • the fluorescence intensity of cilia assessed by means of quantification of ARL-13b, is known to be an indicator of the ciliary function.
  • Epithelial cells were recovered from urine liquid biopsies (URECs) from patients with a LOF mutation in the NPHP1 gene. URECs were isolated by selective trypsinization and proliferated at 37°C with 5% CO2 in “complete medium” supplemented with 10% FBS (fetal bovine serum - Life Technologies). Cells were grown in 75 cm 2 flasks and seeded on glass bottom 96- wells plates. Temperature sensitive immortalized (with thermosensitive SV40 T antigen) URECs were seeded in 96-well glass microplates (Sensoplates, Greiner) at 39 °C for ciliogenesis assays (non-permissive temperature for growth).
  • Cells were exposed to the either taprenepag or compound 1 at final concentration of 1 pM and 0.04% DMSO for 48 hours on the third day of culture. Cells were fixed, and the cilia were stained with anti-ARL13B antibody (Proteintech) and the basal body was stained with mouse anti-gamma tubulin antibody (Sigma). Cells were then incubated at room temperature with secondary antibodies and DAPI. Images were acquired and analyzed using an Opera- Phenix® and Harmony® systems.
  • liver microsomes are subcellular particles derived from the endoplasmic reticulum of hepatic cells. Said microsomes constitute a rich source of drug metabolizing enzymes, including cytochrome P-450. It is herein reported the evolution overtime, the intrinsic clearance (CLint), and the half-life of the tested compounds.
  • the experimental protocol involves pre-incubating the tested compounds with mice liver microsomes (pooled from 250 or more male CD-I mice) in a phosphate buffer at pH 7.4 for 10 minutes at 37°C.
  • the reaction is initiated by adding NADPH and allowing the incubation to proceed for 0, 15, 30, 45, and 60 minutes.
  • the final microsomal protein concentration is standardized at 0.1 mg/mL, and the compounds are tested at a concentration of 0.1 pM with 0.01% DMSO.
  • the incubation mixture is transferred to acctonitnlc/mcthanol/HiO, mixed, and centrifuged.
  • the resulting supernatants are subjected to UHPLC-MS/MS analysis.
  • the analysis involves utilizing an HPLC system equipped with a binary LC pump, autosampler, and C-18 column with a gradient. Peak areas corresponding to the tested compound are recorded, and the remaining compound is determined by comparing the peak area at each time point to the initial time point.
  • the half-life is calculated using the logarithmic curve's initial linear range, assuming first-order kinetics.
  • Taprenepag and omidenepag exhibit relatively high intrinsic clearance (CLint) values (208 and 201 pL/min/mg, respectively), indicating a rapid rate of metabolism within the liver microsomes. Their half-lives, of 33 and 35 minutes respectively, suggest moderate stability in this experimental system.
  • evatanepag showed a significantly higher CLint of 1298 pL/min/mg, indicating a quicker metabolism within the microsomes. This suggests that evatanepag may exhibit a shorter duration of action or increased clearance compared to taprenepag and omidenepag. The notably shorter half-life of 5 minutes further supports this observation.
  • the CLint value was reported as ⁇ 115 pL/min/mg, indicating that the clearance rate was below the detection limit of this assay.
  • the half-life was determined to be greater than 60 minutes, indicating prolonged persistence within the microsomes.

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Abstract

La présente invention concerne le traitement de ciliopathies et de manifestations de ciliopathies, comprenant l'utilisation d'acide 2-(3-(3',4-difluoro-[1,1'-biphényl]-3- ylcarboxamido)phénoxy)acétique (composé 1), ou d'un sel et/ou solvate pharmaceutiquement acceptable de celui-ci.
PCT/EP2024/076112 2023-09-19 2024-09-18 Traitement de ciliopathies et de dysfonctionnements ciliaires Pending WO2025061764A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075369A1 (fr) 2017-10-13 2019-04-18 Alexion Pharmaceuticals, Inc. Méthodes de traitement de maladies associées à des ciliopathies
GB2597731A (en) * 2020-07-31 2022-02-09 Imperial College Innovations Ltd Preterm labour
WO2022074150A1 (fr) * 2020-10-07 2022-04-14 Medetia Agonistes du récepteur de la prostaglandine destinés à être utilisés dans le traitement d'une infection à coronavirus, telle que la maladie d'alzheimer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075369A1 (fr) 2017-10-13 2019-04-18 Alexion Pharmaceuticals, Inc. Méthodes de traitement de maladies associées à des ciliopathies
GB2597731A (en) * 2020-07-31 2022-02-09 Imperial College Innovations Ltd Preterm labour
WO2022074150A1 (fr) * 2020-10-07 2022-04-14 Medetia Agonistes du récepteur de la prostaglandine destinés à être utilisés dans le traitement d'une infection à coronavirus, telle que la maladie d'alzheimer

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COLEMAN R A ET AL: "The affinity, intrinsic activity and selectivity of a structurally novel EP 2 receptor agonist at human prostanoid receptors", vol. 176, no. 5, 4 January 2019 (2019-01-04), UK, pages 687 - 698, XP055839381, ISSN: 0007-1188, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365485/pdf/BPH-176-687.pdf> DOI: 10.1111/bph.14525 *
GANESH PRASANNA ET AL: "Effect of PF-04217329 a prodrug of a selective prostaglandin EPagonist on intraocular pressure in preclinical models of glaucoma", EXPERIMENTAL EYE RESEARCH, ACADEMIC PRESS LTD, LONDON, vol. 93, no. 3, 22 February 2011 (2011-02-22), pages 256 - 264, XP028327982, ISSN: 0014-4835, [retrieved on 20110303], DOI: 10.1016/J.EXER.2011.02.015 *

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