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WO2014082034A1 - Methods for treating irritable bowel syndrome - Google Patents

Methods for treating irritable bowel syndrome Download PDF

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Publication number
WO2014082034A1
WO2014082034A1 PCT/US2013/071678 US2013071678W WO2014082034A1 WO 2014082034 A1 WO2014082034 A1 WO 2014082034A1 US 2013071678 W US2013071678 W US 2013071678W WO 2014082034 A1 WO2014082034 A1 WO 2014082034A1
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snp
amino
alkyl
patient
genotype
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Brian Zambrowicz
Gwenn M. HANSEN
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Lexicon Pharmaceuticals Inc
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Lexicon Pharmaceuticals Inc
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This invention relates to methods for the treatment, management and/or prevention of irritable bowel syndrome using tryptophan hydroxylase inhibitors.
  • IBS Irritable bowel syndrome
  • IBS is a Gl motility disorder that is characterized by abdominal pain or discomfort associated with a change in bowel habits such as constipation (IBS-C), diarrhea (IBS-D), or alternating between the two conditions (IBS-A).
  • IBS-C constipation
  • IBS-D diarrhea
  • IBS-A alternating between the two conditions
  • IBS-M Mixed IBS
  • Diagnostic criteria have been developed which aid the standardized approach to evaluating and diagnosing patients. Criteria that have been established over the previous three decades include: Manning criteria, Rome I, Rome II, and Rome III. See, e.g., Rome III: The Functional Gastrointestinal Disorders. Drossman, D.A., ed. (3 rd edition, January 2006), Appendix A; Drossman, D.A., Gastroenterology 20(5):1377-1390 (2006).
  • 5-Hydroxytryptamine (5-HT) released from the enterochromaffin (EC) cells of the gastrointestinal (Gl) tract is known to play a key role in the normal functioning of the gastrointestinal tract.
  • 5-HT found in the blood is almost entirely derived from the EC cells of the Gl tract. Id. It has been reported that some IBS-D patients have increased levels of blood 5-HT and its metabolite 5- hydroxyindoleacetic acid (5-HIAA) as compared to normal controls. See id.
  • This invention is directed, in part, to methods for the treatment, management, and/or prevention of irritable bowel syndrome, in a patient that is likely to respond to treatment with a TPH inhibitor.
  • the invention is directed to methods or treating, managing, and/or preventing irritable bowel syndrome in a patient that is genotype AA or AC at single nucleotide polymorphism (SNP) rs7130929 and/or is genotype CC or CT at SNP rs4537731 and/or has a genotype at a TPH SNP that is closely linked to one or both of those genotypes.
  • SNP single nucleotide polymorphism
  • the invention is directed to methods of determining whether a patient will respond to treatment with a TPH inhibitor, comprising determining the patient's genotype at SNP rs7130929 and/or SNP rs4537731, wherein a genotype of AA or AC at SNP rs7130929 and/or a genotype of CC or CT at SNP rs4537731 indicates the patient should respond to treatment with a TPH inhibitor.
  • the invention is directed to methods of determining whether a patient will benefit from (i.e., respond to) treatment with a TPH inhibitor, comprising determining the patient's genotype at a TPH SNP, wherein a genotype at the TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731 indicates the patient should benefit from treatment with a TPH inhibitor.
  • methods of treating, managing or preventing IBS comprise administering to a patient a therapeutically or prophylactically effective amount of a tryptoph hydroxylase (TPH) inhibitor.
  • TPH tryptoph hydroxylase
  • Particular TPH inhibitors include compounds of the formula:
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • D is optionally substituted aryl or heterocycle
  • Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl
  • R 4 is hydrogen, alkoxy, amino, amino,
  • a method comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype at a TPH single nucleotide polymorphism (SNP) that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731.
  • the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
  • a method of treating or managing irritable bowel syndrome comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs7130929. In some embodiments, the patient is genotype AA at SNP rs7130929. In some embodiments, a method of treating or managing irritable bowel syndrome (IBS) comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the patient is genotype CC at SNP rs4537731.
  • the patient suffering from IBS may have a genotype selected from CC or CT at SNP rs4537731. In any of the embodiments described herein, the patient suffering from IBS may be genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731.
  • the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731. In some embodiments, a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor.
  • a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy comprises determining a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from AA and AC at SNP rs7130929.
  • the method comprises determining if the patient is genotype AA at SNP rs7130929.
  • a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor.
  • a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy comprises determining a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731.
  • a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor.
  • a method may comprise determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In any of the embodiments described herein, a method may comprise determining if the patient is genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
  • a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype selected from AA and AC at SNP rs7130929. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929. In some
  • the method comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731.
  • the IBS may be diarrhea-predominant IBS
  • the TPH inhibitor may be a compound of the formula:
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • D is optionally substituted aryl or heterocycle
  • Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl
  • R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl
  • each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
  • the compound is of the formula:
  • the compound is of the formula
  • each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyi, aryl, or heterocycle; and E is optionally substituted aryl or heterocycle; and the remaining substituents are defined as above.
  • the TPH inhibitor may be a compound of the formula:
  • each Ri is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;
  • R2 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;
  • R3 is hydrogen, C(0)RA, C(0)ORA, or optionally substituted alkyl, alkyl-aryl, alkyl- heterocycle, aryl, or heterocycle;
  • R 4 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; each RA is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle;
  • each RB is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle;
  • each Rc is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle
  • n 1-4.
  • the compound is of the formula:
  • the compound is of the formula
  • each Rs is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3; and the remaining substituents are defined as above.
  • the compound is of the formula:
  • each R5 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3; and the remaining substituents are defined as above.
  • Ri is hydrogen or halogen.
  • m is 1.
  • R2 is hydrogen or amino.
  • R 4 is hydrogen or CM alkyl.
  • Rs is hydrogen or lower alkyl. In some embodiments, Rs is methyl.
  • the TPH inhibitor is (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2- trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
  • the TPH inhibitor is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate, or a pharmaceutically acceptable salt thereof.
  • the TPH inhibitor is (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows a portion of the 5'-untranslated region of the TPH1 gene showing the locations of single nucleotide polymorphisms (SNPs) rs7130929 and rs4537731. For each SNP, the alternate nucleotides are shown in brackets and underlined at the SNP location. 5.
  • SNPs single nucleotide polymorphisms
  • TPH tryptophan hydroxylase
  • IBS irritable bowel syndrome
  • SNP single nucleotide polymorphism
  • Patients who are genotype CC at SNP rs7130929 and/or are genotype TT at SNP rs4537731 are less likely to respond, even though genotypes CC at SNP rs7130929 and TT at SNP rs4537731 are associated with higher expression of TPH1, and with diarrhea- predominant IBS (IBS-D).
  • IBS-D diarrhea- predominant IBS
  • alkenyl means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond.
  • alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2- butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3- heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl.
  • alkyl means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl.” Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyi moieties have linear, branched and/or cyclic portions (e.g., l-ethyl-4-methyl-cyclohexyl).
  • alkyi includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
  • alkoxy means an -O-alkyl group.
  • alkoxy groups include -OCHs, -OCH2CH3, -0(CH 2 ) 2 CH3, -0(CH 2 ) 3 CH 3 , -0(CH 2 )4CH 3 , and -0(CH 2 ) 5 CH 3 .
  • alkylaryl or "alkyl-aryl” means an alkyi moiety bound to an aryl moiety.
  • alkylheteroaryl or “alkyl-heteroaryl” means an alkyi moiety bound to a heteroaryl moiety.
  • alkylheterocycle or “alkyl-heterocycle” means an alkyi moiety bound to a heterocycle moiety.
  • alkynyl means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond.
  • alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, l-heptynyl, 2-heptynyl, 6-heptynyl, l-octynyl, 2-octynyl, 7-octynyl, l-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
  • aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms.
  • An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include
  • anthracenyl azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.
  • arylalkyl or "aryl-alkyl” means an aryl moiety bound to an alkyi moiety.
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include lower alkyi esters, alkoxyacyloxy esters, alkyi acylamino alkyi esters, and choline esters.
  • biohydrolyzable amides include lower alkyi amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides.
  • biohydrolyzable carbamates include lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • halogen and halo encompass fluorine, chlorine, bromine, and iodine.
  • heteroalkyl refers to an alkyl moiety (e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, 0 or S).
  • heteroaryl means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, 0 or S). Examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,
  • benzoquinazolinyl benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and triazinyl.
  • heteroarylalkyl or “heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.
  • heterocycle refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, 0 or S).
  • a heterocycle may comprise multiple ⁇ i.e., two or more) rings fused or bound together.
  • Heterocycles include heteroaryls.
  • Examples include benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl,
  • heterocyclealkyl or “heterocycle-alkyl” refers to a heterocycle moiety bound to an alkyl moiety.
  • heterocycloalkyl refers to a non-aromatic heterocycle.
  • heterocycloalkylalkyl or “heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to an alkyl moiety.
  • the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder, or of one or more of its symptoms, in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission.
  • the terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.
  • Symptoms of non-constipating IBS include: 1. Recurrent abdominal pain or discomfort, defined as an uncomfortable sensation not described as pain at least 3 days/month and associated with two or more of the following characteristics:
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine,
  • non-toxic acids include inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesul
  • Non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
  • Examples of specific salts thus include hydrochloride and mesylate salts.
  • Others are well-known in the art. See, e.g., Remington' s Pharmaceutical Sciences, 18 th ed. (Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy, 19 th ed. (Mack Publishing, Easton PA: 1995).
  • potent TPH1 inhibitor is a compound that has a TPHlJCso of less than about 10 ⁇ .
  • the terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder, or of one or more of its symptoms.
  • the terms encompass prophylaxis.
  • prodrug encompasses pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters of compounds disclosed herein.
  • prodrugs include compounds that comprise a biohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate, or biohydrolyzable ureide analog).
  • Prodrugs of compounds disclosed herein are readily envisioned and prepared by those of ordinary skill in the art. See, e.g., Design of Prodrugs. Bundgaard, A. Ed., Elsevier, 1985; Bundgaard, H., “Design and Application of Prodrugs," A Textbook of Drug Design and Development. Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review. 1992, 8, 1-38.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • protecting group when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions.
  • Protecting groups are well known in the art. See, e.g., Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis (3 rd ed., John Wiley & Sons: 1999); Larock, R.C., Comprehensive Organic Transformations (2 nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
  • sample refers to any biological material that contains sufficient genetic material to allow genotyping of the SNPs described herein.
  • Nonlimiting exemplary samples include blood, cheek swabs, etc.
  • selective TPH1 inhibitor is a compound that has a TPH2_ICso that is at least about 10 times greater than its TPHlJCso.
  • stereomerically enriched composition of a compound refers to a mixture of the named compound and its stereoisomer(s) that contains more of the named compound than its stereoisomer(s).
  • a stereoisomerically enriched composition of (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and (R)-butan-2- ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10, 95/5, and 98/2.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound.
  • a stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or - alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl,
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition.
  • a therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • TPH single nucleotide polymorphism or "TPH
  • SIMP refers to SNP rs7130929, SNP rs4537731, and other SNPs that are closely linked with SNP rs7130929 and/or SNP rs4537731.
  • a SNP that is "closely linked with SNP rs7130929 and/or SNP rs4537731" is a SNP that tends to be inherited (i.e., is in linkage disequilibrium) with SNP rs7130929 and/or SNP rs4537731.
  • treat contemplate an action that occurs while a patient is suf ering from the specified disease or disorder, which reduces the severity of the disease or disorder, or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
  • one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
  • the phrase "optionally substituted alky, aryl, or heteroaryl” has the same meaning as “optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl.”
  • a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical.
  • the terms “pyridine” and “pyridyl” are accorded the same meaning when used to describe a moiety attached to other chemical moieties.
  • the two phrases “XOH, wherein X is pyridyl” and “XOH, wherein X is pyridine” are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof.
  • any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.
  • chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.
  • This invention encompasses tautomers and solvates (e.g., hydrates) of the compounds disclosed herein. 5.2.
  • TPH inhibitors examples of which are disclosed in U.S. patent nos. 8,093,291; 8,063,057; 7,968,559; 7,875,622; 7,553,840;
  • TPH inhibitors are compounds of the formula:
  • A is optionally substituted cycloalkyi, aryl, or heterocycle
  • A is optionally substituted cycloalkyi, aryl, or heterocycle
  • -C(R 4 ) C(R 4 )-, -C ⁇ C-, -N(Rs)-, -N(R 5 )C(0)N(R 5 )-, -C(R 3 R 4 )N(R 5 )-, -N(R 5 )C(R 3 R 4 )-
  • D is optionally substituted aryl or heterocycle
  • E is optionally substituted aryl or heterocycle
  • Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted al
  • particular compounds include those wherein A is optionally substituted cycloalkyi (e.g., 6-membered and 5-membered).
  • A is optionally substituted aryl (e.g., phenyl or naphthyl).
  • A is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • A is aromatic. In others, A is not aromatic.
  • A is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyi, aryl, or heterocycle.
  • Compounds encompassed by this formula include those wherein Ai and/or A2 is optionally substituted cycloalkyi (e.g., 6-membered and 5-membered).
  • Ai and/or A2 is optionally substituted aryl (e.g., phenyl or naphthyl).
  • Ai and/or A2 is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5- membered heterocycles examples include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • Ai and/or A2 is aromatic. In others, Ai and/or A2 is not aromatic.
  • D is optionally substituted aryl (e.g., phenyl or naphthyl).
  • D is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • D is aromatic. In others, D is not aromatic.
  • D is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • E is optionally substituted aryl (e.g., phenyl or naphthyl).
  • E is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • E is aromatic.
  • E is not aromatic.
  • E is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • R2 is hydrogen or optionally substituted alkyi.
  • n 1 or 2.
  • X is a bond or S.
  • X is -0-, -C(R3R4)0-, or -OC(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, and R4 is hydrogen or optionally substituted alkyi. In some, R3 is hydrogen and R4 is trifluoromethyl.
  • X is -S(02)-, -S(02)N(R 5 )-, -N(R 5 )S(02)- , -C(R3R4)S(02)-, or -S(02)C(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, R4 is hydrogen or optionally substituted alkyi, and Rs is hydrogen or optionally substituted alkyi.
  • X is -N(R 5 )-, -N(R 5 )C(0)N(R 5 )-, -C(R 3 R4)N(R 5 )-, or -N(R 5 )C(R 3 R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, R4 is hydrogen or optionally substituted alkyi, and each Rs is independently hydrogen or optionally substituted alkyi.
  • R3 is trifluoromethyl. Others are encompassed by the formula:
  • R3 is hydrogen
  • each of Zi, Z2, Z3, and Z 4 is independently N or CR6; each R6 is independently hydrogen, cyano, halogen, OR7, NR8R9, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Re is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. Certain such compounds are of the formula:
  • R3 is trifluoromethyl. Others are of the formula:
  • R3 is hydrogen
  • some compounds are such that all of Zi, Z2, Z3, and Z 4 are N. In others, only three of Zi, Z2, Z3, and Z 4 are N. In others, only two of Zi, Z2, Z3, and Z 4 are N. In others, only one of Zi, Z2, Z3, and Z 4 is N. In others, none of Zi, Z2, Z3, and Z 4 are N.
  • R3 is trifluoromethyl. Others are of the formula:
  • R3 is hydrogen
  • some compounds are such that all of ⁇ , Z'2, and Z'3 are N or NH. In others, only two of ⁇ , Z'2, and Z'3 are N or NH. In others, only one of ⁇ , Z'2, and Z'3 is N or NH. In others, none of ⁇ , Z'2, and Z'3 are N or NH.
  • each of ⁇ ' ⁇ , Z n 2, Z n 3, and Z" 4 is independently N or CR10; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ru is independently hydrogen or optionally substituted alkyl, alkyl- aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
  • R3 is trifluoromethyl. Others are of the formula:
  • Z"3, and Z"4 are N. In others, only three of ⁇ ' ⁇ , Z"2, Z' 3, and Z" 4 are N. In others, only two of Z"i, Z" 2 , Z" 3 , and Z" 4 are N. In others, only one of ⁇ ' ⁇ , Z" 2 , Z" 3 , and Z" 4 is N. In others, none of Z"i, Z"2, Z" 3 , and Z" are N.
  • each of ⁇ ' ⁇ , Z n 2, Z n 3, and Z" 4 is independently N or CR10; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ru is independently hydrogen or optionally substituted alkyl, alkyl- aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
  • R3 is trifluoromethyl. Others are of the formula:
  • R3 is hydrogen
  • some compounds are such that all of ⁇ ' ⁇ , Z' 2, Z"3, and Z"4 are N. In others, only three of ⁇ ' ⁇ , Z"2, Z' 3, and Z" 4 are N. In others, only two of Z"i, Z" 2 , Z" 3 , and Z" 4 are N. In others, only one of ⁇ ' ⁇ , Z" 2 , Z" 3 , and Z" 4 is N. In others, none of Z"i, Z"2, Z" 3 , and Z" are N.
  • particular compounds include those wherein both A and E are optionally substituted phenyl and, for example, X is -0-, -C(R3R4)0-, or -OC(R3R 4 )- and, for example, R3 is hydrogen and R 4 is trifluoromethyl and, for example, n is 1.
  • A2 is optionally substituted heterocycle
  • Ri is hydrogen, C(0)RA, C(0)ORA, or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • Rio is halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle
  • each Ri 4 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle
  • RA is hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle
  • RB is hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl
  • each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3.
  • each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-4.
  • Others are of the formula:
  • each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and q is 1-2.
  • each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and q is 1-2.
  • A2 is aromatic. In others, A2 is not aromatic. In some, A2 is optionally substituted with one or more of halogen or lower alkyl. In some, R14 is hydrogen or halogen. In some, m is 1. In some, Rio is hydrogen or amino. In some, Ri is hydrogen or lower alkyl. In others, Ri is C(0)ORA and RA is alkyl. In some, R2 is hydrogen or lower alkyl. In some, R15 is hydrogen or lower alkyl (e.g., methyl). In some, n is i. In some, p is 1. In some, q is 1.
  • Stereoisomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns, chiral resolving agents, or enzymatic resolution. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
  • Particular compounds of the invention are potent TPHl inhibitors.
  • Specific compounds have a TPHlJCso of less than about 10, 5, 2.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 ⁇ .
  • Particular compounds are selective TPHl inhibitors.
  • Specific compounds have a
  • TPHlJCso that is about 10, 25, 50, 100, 250, 500, or 1000 times less than their TPH2_ICso.
  • THP1 inhibitors include:
  • THP1 inhibitors are: (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'- methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-ethyl 2-amino-3-(4-(2- amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoate; and (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoi
  • certain compounds of the invention do not readily cross the blood/brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or 0.01 percent of compound in the blood passes into the brain).
  • the ability or inability of a compound to cross the blood/brain barrier can be determined by methods known in the art. See, e.g., Riant, P. et al., Journal of Neurochemistrv 51:421-425 (1988); Kastin, A.J., Akerstrom, V., J. Pharmacol. Exp. Therapeutics 294:633-636 (2000); W. A. Banks, W.A., et al., J. Pharmacol. Exp. Therapeutics 302:1062-1069 (2002).
  • compositions comprising one or more of the TPH1 inhibitors described herein are provided.
  • Certain pharmaceutical compositions are single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or nonaqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or
  • the formulation should suit the mode of administration.
  • the oral administration of a compound susceptible to degradation in the stomach may be achieved using an enteric coating.
  • a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action.
  • compounds may be administered in liposomal formulations in order to protect them from degradative enzymes, facilitate transport in circulatory system, and effect their delivery across cell membranes.
  • poorly soluble compounds may be incorporated into liquid dosage forms (and dosage forms suitable for reconstitution) with the aid of solubilizing agents, emulsifiers and surfactants such as, but not limited to, cyclodextrins (e.g., a-cyclodextrin, ⁇ -cyclodextrin, Captisol®, and EncapsinTM (see, e.g., Davis and Brewster. Nat. Rev. Drug Disc.
  • solubilizing agents e.g., a-cyclodextrin, ⁇ -cyclodextrin, Captisol®, and EncapsinTM (see, e.g., Davis and Brewster. Nat. Rev. Drug Disc.
  • non-aqueous solvents such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide
  • DMSO methyl methacrylate
  • biocompatible oils e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils
  • glycerol e.g., tetrahydrofurfuryl alcohol
  • polyethylene glycols e.g., polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof (e.g., DMSO:cornoil).
  • Nanoparticles of a compound may be suspended in a liquid to provide a nanosuspension (see, e.g., Rabinow, Nature Rev. Drug Disc. 3:785-796 (2004)).
  • Nanoparticle forms of compounds described herein may be prepared by the methods described in U.S. Patent Publication Nos. 2004-0164194, 2004-0195413, 2004-0251332, 2005-0042177 Al, 2005-0031691 Al, and U.S. Patent Nos. 5,145,684, 5,510,118,
  • the nanoparticle form comprises particles having an average particle size of less than about 2000 nm, less than about 1000 nm, or less than about 500 nm.
  • composition, shape, and type of a dosage form will typically vary depending with use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. How to account for such differences will be apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • compositions suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.
  • Such dosage forms can be prepared by conventional methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets).
  • Parenteral dosage forms can be administered to patients by various routes including subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include: Water for Injection USP; aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • This invention encompasses methods of treating IBS patients who are more likely to respond to TPH inhibitor therapy. Applicants have discovered that for non-constipating IBS, patients that are genotype AA or AC at SNP rs7130929 and/or are genotype CC or CT at SNP rs4537731 are more likely to respond to TPH inhibitory therapy. Response can be measured by global relief of symptoms or by stool consistency.
  • methods of treating, managing and/or preventing irritable bowel syndrome comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • methods of treating, managing and/or preventing irritable bowel syndrome comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • methods of treating, managing and/or preventing irritable bowel syndrome (IBS), including diarrhea-predominant IBS (IBS-D) and mixed IBS (IBS-A) comprise
  • TPH inhibitor administering to a patient in need thereof a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • exemplary TPH inhibitors are the compounds disclosed herein.
  • Some embodiments encompass a method of treating or managing irritable bowel syndrome (IBS), which comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has been determined to be genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • the patient suffering from IBS has been determined to have a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • a patient suffering from IBS such as non-constipating IBS, diarrhea-predominant IBS (IBS-D), and mixed IBS (IBS- A)
  • IBS-D diarrhea-predominant IBS
  • IBS- A mixed IBS
  • a patient suffering from IBS such as non-constipating IBS, diarrhea-predominant IBS (IBS-D), and mixed IBS (IBS-A)
  • IBS-D diarrhea-predominant IBS
  • IBS-A mixed IBS
  • the genotype of the patient at a TPH SNP may be determined by any method.
  • methods of treating and/or managing IBS comprise administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has been determined to be genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • the patient suffering from IBS has been determined to have a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • the patient is suffering from non-constipating IBS, such as IBS-D or IBS-A.
  • the patient is suffering from diarrhea-predominant IBS (IBS-D).
  • the TPH inhibitor is administered orally. In some, the TPH inhibitor is administered twice (BID) or three times (TID) daily.
  • methods of determining whether a patient will respond to treatment with a TPH inhibitor comprise determining the patient's genotype at a TPH SNP. In some such embodiments, the method comprises determining the patient's genotype at SNP rs7130929 and/or at SNP rs4537731. In some embodiments, genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731, or a genotype at a TPH SNP that is closely linked to one of those genotypes, indicates that the patient may respond to treatment with a TPH inhibitor.
  • genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731, or a genotype at a TPH SNP that is closely linked to one of those genotypes indicates that the patient may respond to treatment with a TPH inhibitor.
  • a patient is considered to respond to treatment with a TPH inhibitor when the patient's symptoms improve or do not worsen.
  • a method of determining if a patient suffering from IBS will be responsive to TPH inhibitor therapy comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of: improvement with defecation, onset associated with a change in frequency of stool, or onset associated with a change in form (appearance) of stool; and b) if the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • the method comprises determining if the patient is genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from IBS will be responsive to TPH inhibitor therapy comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of: improvement with defecation, onset associated with a change in frequency of stool, or onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731.
  • the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
  • the IBS may be non-constipating IBS, diarrhea- predominant IBS (IBS-D), or mixed IBS (IBS-A).
  • IBS-D diarrhea- predominant IBS
  • IBS-A mixed IBS
  • the genotype of a patient at SNP rs7130929 and/or SNP rs4537731 and/or another TPH SNP may be determined using any of a variety of nucleic acid techniques known, including but not limited to, nucleic acid sequencing and genotyping by various methods, including hybridization-based genotyping methods, enzyme-based genotyping methods, and genotyping methods based on physical properties of DNA. Any suitable method of sequencing nucleic acids may be used to determine the genotype of a patient.
  • Non-limiting examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing, dye terminator sequencing, pyrosequencing, sequencing-by-ligation, single molecule sequencing, single-base addition sequencing, sequence-by-synthesis (SBS), massive parallel clonal, massive parallel single molecule SBS, massive parallel single molecule real-time, massive parallel single molecule real-time nanopore technology, DNA nanoball sequencing, ion semiconductor sequencing, etc. See, e.g., Sanger et al., Proc. Natl. Acad. Sci. USA 74:5463-5467 (1997); Maxam et al., Proc. Natl. Acad. Sci.
  • Any suitable method of genotyping may be used to determine the genotype at SNPs rs7130929 and rs4537731.
  • Nonlimiting exemplary genotyping methods are reviewed, for example, in Kwok et al., Curr. Issues Mol. Biol. 5: 43-60 (2003); and Kim et al., Ann. Rev.
  • Hybridization-based genotyping methods include, but are not limited to, dynamic allele-specific hybridization (DASH), which detects a genotype based on differences in melting temperature that result from mismatched base pairs; molecular beacons, which use hairpins comprising a dye and a quencher that will fluoresce only in the presence of a target sequence (such as a particular genotype); single-nucleotide polymorphism microarrays; and Southern blotting.
  • DASH dynamic allele-specific hybridization
  • molecular beacons which use hairpins comprising a dye and a quencher that will fluoresce only in the presence of a target sequence (such as a particular genotype); single-nucleotide polymorphism microarrays; and Southern blotting.
  • DASH dynamic allele-specific hybridization
  • molecular beacons which use hairpins comprising a dye and a quencher that will fluoresce only in the presence of a target sequence (such as a particular genotype
  • Enzyme-based genotyping methods include, but are not limited to, restriction fragment length polymorphism, in which the presence of SNPs result in different restriction digest patterns; PCR-based genotyping, using, for example, SNP-specific primers; flap endonuclease (FEN)-based methods (such as the Invader® assay and Serial Invasive Signal Amplification Reaction (SISAR) assay), in which a SNP-specific tripartite structure is formed and cleaved by FEN; primer extension-based genotyping (such as the Infinium® assay, APEX assay, and APEX-2 assay), in which a primer is hybridized near the SNP and a single-base extension reaction, in some instances with a labeled nucleoside, is used to determine the genotype; mass spectrometer-based assays (such as iPLEX SNP genotyping assay, Sequenom), in which the identity of the single base addition is determined by mass spectrometry rather than a detectable label; 5'
  • Genotyping methods based on physical properties of DNA include, but are not limited to, single- strand conformation polymorphism, in which SNP-dependent differences in the tertiary folding of a single-stranded DNA are detected; temperature gradient gel electrophoresis, in which SNPs are detected based on differences in the rate that a double-stranded DNA travels when it comprises a mismatch; denaturing high-performance liquid chromatography, in which differences in melting temperatures are detected by retention time in the column; high- resolution melting of an amplicon, in which differences in melting temperature of a DNA amplicon are detected; and SNPlex (Life Technologies, Carlsbad, CA). See, e.g., Costabile et al., Hum Mutat. 27(12):1163-73(2006); Rapley and Harbron, Molecular Analysis and Genome
  • At least one region of the genome comprising SNP rs7130929 and/or SNP rs4537731 is amplified. In some embodiments, at least one region is amplified prior to sequencing and/or SNP detection. Any suitable method of amplification may be used. Nonlimiting exemplary methods of nucleic acid amplification include the polymerase chain reaction (PCR), transcription mediated amplification (TMA), ligase chain reaction (LCR), strand- displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). See, e.g., Mullis et al., Meth. Enzymol.
  • PCR polymerase chain reaction
  • TMA transcription mediated amplification
  • LCR ligase chain reaction
  • SDA strand- displacement amplification
  • NASBA nucleic acid sequence based amplification
  • a computer-based analysis program is used to translate the raw data generated by the detection assay (e.g., the identity, presence, or absence of a particular allele at rs7130929 and/or rs4537731 and/or at another TPH SNP) into data of predictive value for a clinician.
  • the clinician can access the predictive data using any suitable means.
  • the present invention provides the further benefit that the clinician, who may not be trained in genetics or molecular biology, need not understand the raw data.
  • the data is presented directly to the clinician in its most useful form. The clinician is then able to immediately utilize the information in order to optimize the care of the patient.
  • a sample such as a blood sample
  • a profiling service e.g., clinical lab at a medical facility, genomic profiling business, etc.
  • a profiling service located in any part of the world (e.g., in a country different than the country where the patient resides, where the sample is obtained from the patient, or where the information is ultimately used) to generate raw data.
  • the patient may visit a medical center to have the sample obtained and sent to the profiling center, or, in some instances, patients may collect the sample themselves (e.g., a urine or fecal sample) and directly send it to a profiling center.
  • a profile is produced (e.g., the identity, presence, or absence of a particular allele at rs7130929 and/or rs4537731 and/or at another TPH SNP).
  • the profile data is then prepared in a format suitable for interpretation by a treating clinician.
  • the prepared format may represent a diagnosis or risk assessment for the patient (e.g., an indication that the patient is more likely, or less likely, to respond to treatment with TPH inhibitor), along with recommendations for particular treatment options.
  • the data may be displayed to the clinician by any suitable method.
  • the profiling service generates a report that can be printed for the clinician (e.g., at the point of care) or displayed to the clinician on a computer monitor.
  • the raw data is provided to the point of care facility or other regional facility.
  • the receiving facility further analyzes and/or converts the raw data to information useful for a clinician or patient.
  • the patient is able to directly access the data using the electronic communication system.
  • the patient may chose further intervention or counseling based on the results.
  • the data is used for research use.
  • the data may be used to further optimize the inclusion or elimination of markers as useful indicators of a particular condition or stage of disease, or as a predictor of response to treatment.
  • the data analysis and transmission may be implemented in various forms of hardware, software, firmware, processors, distributed servers (e.g., as used in cloud computing) or a combination thereof.
  • the methods and systems described herein can be implemented as a combination of hardware and software.
  • the software can be implemented as an application program tangibly embodied on a program storage device, or different portions of the software implemented in the user's computing environment (e.g., as an applet) and on the reviewer's computing environment, where the reviewer may be located at a remote site (e.g., at a service provider's facility).
  • part or all of the input and output data can be sent electronically or telephonically (e.g., by facsimile, e.g., using devices such as fax back).
  • all or a portion of the input data and/or all or a portion of the output data are maintained on a server for access, e.g., confidential access. The results may be accessed or sent to professionals as desired.
  • kits for determining whether a patient suffering from IBS will be responsive to TPH inhibitor therapy, which comprise reagents for determining a patient's genotype at SNP rs7130929 and/or at SNP rs4537731 and/or at another TPH SNP.
  • kits may include primers, controls, enzymes, buffers, and the like.
  • a randomized, double-blind, placebo-controlled phase 2a clinical trial was conducted to assess the safety and efficacy of a TPH inhibitor, (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro- l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, in 155 patients suffering from IBS-D or IBS-A, based on Rome III criteria. Capsules containing the compound or placebo were orally administered. Two dose levels were tested: 250 mg QID and 1000 mg QID. A two-week run-in period was used to establish baseline symptoms, followed by a 28 day randomized, double-blind treatment period. There was then a two-week follow-up period.
  • the TPHl promoter contains the SNPs rs7130929 and rs4537731.
  • Figure 1 shows a portion of the 5' untranslated region of the TPHl gene with the location of the SNPs indicated.
  • the CC genotype at rs7130929 in the TPHl promoter correlates with higher expression of TPHl.
  • the AA genotype at rs7130929 in the TPHl promoter correlates with lower expression of TPHl, while the CA genotype correlates with intermediate expression.
  • the TT genotype correlates with higher expression of TPHl
  • the CC genotype correlates with lower expression of TPHl
  • the CT genotype correlates with intermediate expression. See, e.g., Sun et al., Alcohol Clin Exp Res, 29(1): 1-7 (2005); Rotondo et al., Mol.
  • the CC genotype at rs7130929 and the TT genotype at rs4537731 would also be markers for response to TPH inhibitors, such as (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl- 4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, which are effective in IBS-D.
  • TPH inhibitors such as (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl- 4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, which are effective in IBS-D.
  • one hundred and five blood samples from the phase 2a clinical trial were genotyped at the rs7130929 and rs4357731 SNPs located in the TPHl promoter, as follows.
  • PCR was performed with Kapa 2G Fast DNA polymerase (KAPA Biosystems KK5021) according to manufacturer's instructions using primers 5'- TTGGGATAAGGAGCTAATCGACTGA-3' (SEQ ID NO: 1) and 5'-TGCGTGTATCTGACTGGTG-3' (SEQ ID NO: 2). Briefly, -lOOng of genomic DNA template was used for each 25 ⁇ reaction containing lx reaction buffer, 0.2mM dNTPs, 3 mM MgC , 0.5 ⁇ primers, and 0.5 Units of KSPA2G Fast DNA polymerase.
  • Reactions were cycled as follows: Denature at 95°C for 2 minutes followed by 35 cycles of 95°C for 20 seconds, 60°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute.
  • Reaction products were purified by passing through Sephacryl- 300-HR (Sigma S300HR) and Sephadex G-50 (GE Health 17-0042-02) columns. A total of 2 ⁇ purified DNA was used for Sanger sequencing with the same primers used for PCR.
  • PCR was repeated on all samples using iProof High fidelity DNA polymerase (Bio-Rad 172-5301) according to manufacturer's instructions using the same primers used above. Briefly, -100 ng of genomic DNA was used for each 20 ⁇ reaction containing lx iProof HF buffer, 0.2 mM dNTPs, 0.5 ⁇ primers, and 0.5 Units iProof high fidelity DNA polymerase. Reactions were cycled as follows: Denature at 98°C for 2 minutes followed by 35 cycles of 98°C for 15 seconds, 61°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute.
  • Reaction products were purified by first adding 10 ⁇ of H2O followed by passing through Sephacryl-300 and Sephadex G-50 columns. A total of 2 ⁇ purified DNA was used for Sanger sequencing with nested primers 5'- ATAAG G AGCTAATCG ACTG ACTACT-3 ' (SEQ ID NO: 3) and 5'-CTAACACTGAACAATCCAGA-3' (SEQ ID NO: 4).
  • TTATG GCATTG AAGTAAG AGCAC-3 ' (SEQ ID NO: 5) and 5 '-G GTATTTACTG GTTG AGTAGTC-3 ' (SEQ ID NO: 6).
  • -100 ng of genomic DNA template was used for each 25 ⁇ reaction containing lx reaction buffer, 0.2 mM dNTPs, 3 mM MgCb, 0.5 ⁇ primers, and 0.5 Units of KAPA2G Fast DNA polymerase. Reactions were cycled as follows: Denature at 95°C for 2 minutes followed by 35 cycles of 95°C for 20 seconds, 57°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute.
  • Reaction products were purified by passing through Sephacryl-300-HR (Sigma S300HR) and Sephadex G-50 (GE Health 17-0042-02) columns. A total of 2 ⁇ purified DNA was used for Sanger sequencing with the same primers used for PCR.
  • TTATGGCATTGAAGTAAGAGCAC-3 SEQ ID NO: 5
  • 5'-TGCGTGTATCTG ACTG GTG-3 ' SEQ ID NO: 2
  • Nested primers 5'-GCATTGAAGTAAGAGCACTGGAT-3' SEQ ID NO: 7
  • 5'-GTG AATGTTAG GCCGTCCTTAACCA-3 ' SEQ ID NO: 8 are employed in the 2nd round of PCR.
  • PCR products are cleaned by passing through Sephacryl-300 and Sephadex G-50 columns then cloned with Zero Blunt Topo blunt PCR cloning kit (Invitrogen K287540). Cloned products are sequenced using the T7 primer 5'-TAATACGACTCACTATAGGG-3' (SEQ ID NO: 9) present in the vector. In some embodiments, this method resolves the discrepancy discussed below between PCR and SNP analysis for some samples. In some embodiments, the discrepancy may be due to a SNP in certain samples affecting the annealing efficiency of certain commercial primers. Sequencing
  • Sequencing reactions were prepared in 10 ⁇ volume with 0.5 ⁇ of BigDye Terminator vl.l premix (Applied Biosystems) in lx reaction buffer and 3.2 pmol primer. Reactions were cycled as follows: Denature at 94°C for 3 minutes followed by 36 cycles of 94°C for 35 seconds, 52°C for 25 seconds, and 60°C for 2 minutes, followed by a 60°C hold for 3 minutes and a 4°C hold for 1 minute. Unincorporated dye terminators were removed from completed reactions by first adding 15 ⁇ of H2O followed by passing through Sephadex G-50 columns. After addition of EDTA to a final concentration of 0.2 mM, the purified products were subjected to DNA Analyzer ABI Prism 3730x1 (Applied Biosystems).
  • SNP reactions were prepared using SNP Genotyping Assay kits from ABI
  • samples 20 and 30 Two of the samples (samples 20 and 30) produced different results by sequencing and SNP analysis. In each case, the sample was genotype AC by sequencing and CC by SNP analysis. Those samples were considered to be inconclusive. Table 2 shows the prevalence of each genotype in the sample set.
  • Table 4 shows the prevalence of each genotype in the sample set.
  • Table 4 rs4537731 genotype prevalence The genotype prevalence in the responder subset and non-responder subset of a portion of the study population is shown in Table 5.
  • the higher expressing genotypes, CC at rs7130929 and TT at rs4537731 were found to be underrepresented in the responder population.

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Abstract

This invention relates to methods of treating irritable bowel syndrome using tryptophan hydroxylase (TPH) inhibitors in patients is predicted to respond to treatment with a TPH inhibitor.

Description

METHODS FOR TREATING IRRITABLE BOWEL SYNDROME
1. FIELD OF THE INVENTION
This invention relates to methods for the treatment, management and/or prevention of irritable bowel syndrome using tryptophan hydroxylase inhibitors.
2. BACKGROUND
Irritable bowel syndrome (IBS) is the most common diagnosis made by
gastroenterologists, and one of the most common disorders in the general population, with prevalence rates estimated at 10-15% of the U.S. population. IBS is a Gl motility disorder that is characterized by abdominal pain or discomfort associated with a change in bowel habits such as constipation (IBS-C), diarrhea (IBS-D), or alternating between the two conditions (IBS-A). Mixed IBS (IBS-mixed or IBS-M) is used to define a subset of patients with IBS who at any one time exhibit symptoms of both diarrhea and constipation. This distinguishes IBS-M patients from IBS-A patients where the latter alternate between exhibiting features of IBS-D and IBS-C over periods of time.
Diagnostic criteria have been developed which aid the standardized approach to evaluating and diagnosing patients. Criteria that have been established over the previous three decades include: Manning criteria, Rome I, Rome II, and Rome III. See, e.g., Rome III: The Functional Gastrointestinal Disorders. Drossman, D.A., ed. (3rd edition, January 2006), Appendix A; Drossman, D.A., Gastroenterology 20(5):1377-1390 (2006).
5-Hydroxytryptamine (5-HT) released from the enterochromaffin (EC) cells of the gastrointestinal (Gl) tract is known to play a key role in the normal functioning of the gastrointestinal tract. Atkinson, W. et al., Gastroenterology 130:34-43, 34 (2006). 5-HT found in the blood is almost entirely derived from the EC cells of the Gl tract. Id. It has been reported that some IBS-D patients have increased levels of blood 5-HT and its metabolite 5- hydroxyindoleacetic acid (5-HIAA) as compared to normal controls. See id.
3. SUMMARY OF THE INVENTION
This invention is directed, in part, to methods for the treatment, management, and/or prevention of irritable bowel syndrome, in a patient that is likely to respond to treatment with a TPH inhibitor. In some embodiments, the invention is directed to methods or treating, managing, and/or preventing irritable bowel syndrome in a patient that is genotype AA or AC at single nucleotide polymorphism (SNP) rs7130929 and/or is genotype CC or CT at SNP rs4537731 and/or has a genotype at a TPH SNP that is closely linked to one or both of those genotypes. In some embodiments, the invention is directed to methods of determining whether a patient will respond to treatment with a TPH inhibitor, comprising determining the patient's genotype at SNP rs7130929 and/or SNP rs4537731, wherein a genotype of AA or AC at SNP rs7130929 and/or a genotype of CC or CT at SNP rs4537731 indicates the patient should respond to treatment with a TPH inhibitor. In some embodiments, , the invention is directed to methods of determining whether a patient will benefit from (i.e., respond to) treatment with a TPH inhibitor, comprising determining the patient's genotype at a TPH SNP, wherein a genotype at the TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731 indicates the patient should benefit from treatment with a TPH inhibitor.
In some embodiments, methods of treating, managing or preventing IBS comprise administering to a patient a therapeutically or prophylactically effective amount of a tryptoph hydroxylase (TPH) inhibitor. Particular TPH inhibitors include compounds of the formula:
Figure imgf000003_0001
and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond (i.e., A is directly bound to D), -0-, -S-, -C(O)-, -C(R4)=, =C(R4)- , -C(R3R4)-, -C(R4)=C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-
, -ONC(Rs)-, -C(R3)NO-, -C(R3R4)0-, -OC(R3R4)-, -S(02)-, -S(02)N(R5)-, -N(R5)S(02)-, -C(R3R4)S(02)-, or -S(02)C(R3R4)-; D is optionally substituted aryl or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each Rs is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
In some embodiments, methods of treating or managing irritable bowel syndrome (IBS) are provided. In some embodiments, a method comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype at a TPH single nucleotide polymorphism (SNP) that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731. In some embodiments, the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
In some embodiments, a method of treating or managing irritable bowel syndrome (IBS) comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs7130929. In some embodiments, the patient is genotype AA at SNP rs7130929. In some embodiments, a method of treating or managing irritable bowel syndrome (IBS) comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the patient is genotype CC at SNP rs4537731.
In any of the embodiments described herein, the patient suffering from IBS may have a genotype selected from CC or CT at SNP rs4537731. In any of the embodiments described herein, the patient suffering from IBS may be genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy is provided. In some embodiments, a method comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731. In some embodiments, a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor.
In some embodiments, a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy comprises determining a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from AA and AC at SNP rs7130929. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929. In some
embodiments, a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor.
In some embodiments, a method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy comprises determining a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of i) improvement with defecation, ii) onset associated with a change in frequency of stool, or iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731. In some embodiments, a method further comprises administering to the patient a therapeutically or prophylactically effective amount of a TPH inhibitor. In any of the embodiments described herein, a method may comprise determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In any of the embodiments described herein, a method may comprise determining if the patient is genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy is provided. In some embodiments, a method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype selected from AA and AC at SNP rs7130929. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929. In some
embodiments, the method comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype CC at SNP rs4537731.
In any of the embodiments described herein, the IBS may be diarrhea-predominant IBS
(IBS-D).
In any of the embodiments described herein, the TPH inhibitor may be a compound of the formula:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -0-, -S-, -C(O)-, -C(R )=, =C(R )-, -C(R3R4)-, -C(R )=C(R )-, -C≡C-, -N(R5)- , -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(Rs)-, -C(R3)NO-, -C(R3R4)0-, -OC(R3R4)- , -S(02)-, -S(02)N(R5)-, -N(R5)S(02)-, -C(R3R4)S(02)-, or -S(02)C(R3R4)-;
D is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;
each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
In some embodiments, the compound is of the formula:
Figure imgf000006_0001
wherein the substituents are defined as above.
In some embodiments, the compound is of the formula
Figure imgf000006_0002
wherein each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyi, aryl, or heterocycle; and E is optionally substituted aryl or heterocycle; and the remaining substituents are defined as above.
In any of the embodiments described herein, the TPH inhibitor may be a compound of the formula:
Figure imgf000006_0003
wherein:
each Ri is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;
R2 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;
R3 is hydrogen, C(0)RA, C(0)ORA, or optionally substituted alkyl, alkyl-aryl, alkyl- heterocycle, aryl, or heterocycle;
R4 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; each RA is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle;
each RB is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle;
each Rc is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and
m is 1-4.
In some embodiments, the compound is of the formula:
Figure imgf000007_0001
wherein the substituents are defined as above.
In some embodiments, the compound is of the formula
Figure imgf000007_0002
wherein:
each Rs is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3; and the remaining substituents are defined as above.
In some embodiments, the compound is of the formula:
Figure imgf000007_0003
wherein:
each R5 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3; and the remaining substituents are defined as above. In some embodiments, Ri is hydrogen or halogen. In some embodiments, m is 1. In some embodiments, R2 is hydrogen or amino. In some embodiments, R4 is hydrogen or CM alkyl. In some embodiments, Rs is hydrogen or lower alkyl. In some embodiments, Rs is methyl.
In some embodiments, the TPH inhibitor is (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2- trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the TPH inhibitor is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate, or a pharmaceutically acceptable salt thereof. In some embodiments, the TPH inhibitor is (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
4. BRIEF DESCRIPTION OF THE FIGURE
Figure 1 shows a portion of the 5'-untranslated region of the TPH1 gene showing the locations of single nucleotide polymorphisms (SNPs) rs7130929 and rs4537731. For each SNP, the alternate nucleotides are shown in brackets and underlined at the SNP location. 5. DETAILED DESCRIPTION
This invention is based, in part, on discoveries made during the first human clinical trials of a tryptophan hydroxylase (TPH) inhibitor for the treatment of IBS. When administered, TPH inhibitors lower the production of serotonin (5-HT) in the gastrointestinal tract. In addition, it has been found that patients with irritable bowel syndrome (IBS) who are genotype AA or AC at single nucleotide polymorphism (SNP) rs7130929 and/or are genotype CC or CT at SNP rs4537731 are more likely to respond to treatment with a TPH inhibitor such as those described herein. Patients who are genotype CC at SNP rs7130929 and/or are genotype TT at SNP rs4537731 are less likely to respond, even though genotypes CC at SNP rs7130929 and TT at SNP rs4537731 are associated with higher expression of TPH1, and with diarrhea- predominant IBS (IBS-D).
5.1. Definitions
Unless otherwise indicated, the term "alkenyl" means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2- butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3- heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl.
Unless otherwise indicated, the term "alkyl" means a straight chain, branched and/or cyclic ("cycloalkyl") hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl." Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyi moieties have linear, branched and/or cyclic portions (e.g., l-ethyl-4-methyl-cyclohexyl). The term "alkyi" includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
Unless otherwise indicated, the term "alkoxy" means an -O-alkyl group. Examples of alkoxy groups include -OCHs, -OCH2CH3, -0(CH2)2CH3, -0(CH2)3CH3, -0(CH2)4CH3, and -0(CH2)5CH3.
Unless otherwise indicated, the term "alkylaryl" or "alkyl-aryl" means an alkyi moiety bound to an aryl moiety.
Unless otherwise indicated, the term "alkylheteroaryl" or "alkyl-heteroaryl" means an alkyi moiety bound to a heteroaryl moiety.
Unless otherwise indicated, the term "alkylheterocycle" or "alkyl-heterocycle" means an alkyi moiety bound to a heterocycle moiety.
Unless otherwise indicated, the term "alkynyl" means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond. Representative alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, l-heptynyl, 2-heptynyl, 6-heptynyl, l-octynyl, 2-octynyl, 7-octynyl, l-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
Unless otherwise indicated, the term "aryl" means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms. An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include
anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.
Unless otherwise indicated, the term "arylalkyl" or "aryl-alkyl" means an aryl moiety bound to an alkyi moiety.
Unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureido" and "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include lower alkyi esters, alkoxyacyloxy esters, alkyi acylamino alkyi esters, and choline esters. Examples of biohydrolyzable amides include lower alkyi amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides. Examples of biohydrolyzable carbamates include lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
Unless otherwise indicated, the terms "halogen" and "halo" encompass fluorine, chlorine, bromine, and iodine.
Unless otherwise indicated, the term "heteroalkyl" refers to an alkyl moiety (e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, 0 or S).
Unless otherwise indicated, the term "heteroaryl" means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, 0 or S). Examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,
benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and triazinyl.
Unless otherwise indicated, the term "heteroarylalkyl" or "heteroaryl-alkyl" means a heteroaryl moiety bound to an alkyl moiety.
Unless otherwise indicated, the term "heterocycle" refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, 0 or S). A heterocycle may comprise multiple {i.e., two or more) rings fused or bound together. Heterocycles include heteroaryls. Examples include benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.
Unless otherwise indicated, the term "heterocyclealkyl" or "heterocycle-alkyl" refers to a heterocycle moiety bound to an alkyl moiety.
Unless otherwise indicated, the term "heterocycloalkyl" refers to a non-aromatic heterocycle.
Unless otherwise indicated, the term "heterocycloalkylalkyl" or "heterocycloalkyl-alkyl" refers to a heterocycloalkyl moiety bound to an alkyl moiety.
Unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder, or of one or more of its symptoms, in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.
Unless otherwise indicated, the term "patient suffering from IBS" means a patient who exhibits symptoms of IBS (e.g., as defined in Rome III criteria). Symptoms of non-constipating IBS (i.e., IBS-D and/or IBS-A) include: 1. Recurrent abdominal pain or discomfort, defined as an uncomfortable sensation not described as pain at least 3 days/month and associated with two or more of the following characteristics:
. Improvement with defecation.
i. Onset associated with a change in frequency of stool.
iii. Onset associated with a change in form (appearance) of stool.
2. Loose or watery stools for at least 25% of bowel movements and hard or lumpy stools for <25% of bowel movements (IBS-diarrhea), or loose or watery stools for at least 25% and hard or lumpy stool for at least 25% of bowel movements (IBS- mixed).
Unless otherwise indicated, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art. See, e.g., Remington' s Pharmaceutical Sciences, 18th ed. (Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton PA: 1995).
Unless otherwise indicated, the term "potent TPH1 inhibitor" is a compound that has a TPHlJCso of less than about 10 μΜ.
Unless otherwise indicated, the terms "prevent," "preventing" and "prevention" contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder, or of one or more of its symptoms. The terms encompass prophylaxis.
Unless otherwise indicated, the term "prodrug" encompasses pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters of compounds disclosed herein. Examples of prodrugs include compounds that comprise a biohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate, or biohydrolyzable ureide analog). Prodrugs of compounds disclosed herein are readily envisioned and prepared by those of ordinary skill in the art. See, e.g., Design of Prodrugs. Bundgaard, A. Ed., Elsevier, 1985; Bundgaard, H., "Design and Application of Prodrugs," A Textbook of Drug Design and Development. Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review. 1992, 8, 1-38.
Unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A prophylactically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
Unless otherwise indicated, the term "protecting group" or "protective group," when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions. Protecting groups are well known in the art. See, e.g., Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis (3rd ed., John Wiley & Sons: 1999); Larock, R.C., Comprehensive Organic Transformations (2nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
Unless otherwise indicated, the term "sample" refers to any biological material that contains sufficient genetic material to allow genotyping of the SNPs described herein.
Nonlimiting exemplary samples include blood, cheek swabs, etc.
Unless otherwise indicated, the term "selective TPH1 inhibitor" is a compound that has a TPH2_ICso that is at least about 10 times greater than its TPHlJCso.
Unless otherwise indicated, the term "stereomerically enriched composition of" a compound refers to a mixture of the named compound and its stereoisomer(s) that contains more of the named compound than its stereoisomer(s). For example, a stereoisomerically enriched composition of (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and (R)-butan-2- ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10, 95/5, and 98/2.
Unless otherwise indicated, the term "stereoisomeric mixture" encompasses racemic mixtures as well as stereomerically enriched mixtures (e.g., R/S = 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and 70/30).
Unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound. A stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
Unless otherwise indicated, the term "substituted," when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or - alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CONH2, as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl (e.g., -CCI3, -CF3, -C(CF3)3), heteroalkyl, hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxygen {i.e., to provide an oxo group), phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether) and urea (-NHCONH-alkyl-).
Unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
Unless otherwise indicated, the term "TPH single nucleotide polymorphism" or "TPH
SIMP" refers to SNP rs7130929, SNP rs4537731, and other SNPs that are closely linked with SNP rs7130929 and/or SNP rs4537731. Unless otherwise indicated, a SNP that is "closely linked with SNP rs7130929 and/or SNP rs4537731" is a SNP that tends to be inherited (i.e., is in linkage disequilibrium) with SNP rs7130929 and/or SNP rs4537731.
Unless otherwise indicated, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a patient is suf ering from the specified disease or disorder, which reduces the severity of the disease or disorder, or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
Unless otherwise indicated, the term "include" has the same meaning as "include" and the term "includes" has the same meaning as "includes, but is not limited to." Similarly, the term "such as" has the same meaning as the term "such as, but not limited to."
Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns. For example, the phrase "optionally substituted alky, aryl, or heteroaryl" has the same meaning as "optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl."
It should be noted that a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical. For example, the terms "pyridine" and "pyridyl" are accorded the same meaning when used to describe a moiety attached to other chemical moieties. Thus, the two phrases "XOH, wherein X is pyridyl" and "XOH, wherein X is pyridine" are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.
It should also be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it. Similarly, names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof. Moreover, any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences. In addition, chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit. This invention encompasses tautomers and solvates (e.g., hydrates) of the compounds disclosed herein. 5.2. Compounds
Methods and compositions of this invention utilize TPH inhibitors, examples of which are disclosed in U.S. patent nos. 8,093,291; 8,063,057; 7,968,559; 7,875,622; 7,553,840;
7,723,345; and 7,709,493.
Particular TPH inhibitors are compounds of the formula:
Figure imgf000015_0001
and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted cycloalkyi, aryl, or heterocycle; X is a bond, -0-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)- , -C(R4)=C(R4)-, -C≡C-, -N(Rs)-, -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)- , -ONC(Rs)-, -C(R3)NO-, -C(R3R4)0-, -OC(R3R4)-, -S(02)-, -S(02)N(R5)-, -N(R5)S(02)-, -C(R3R4)S(02)-, or -S(02)C(R3R4)-; D is optionally substituted aryl or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each Rs is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
Particular compounds are of the formula:
Figure imgf000015_0002
Also encompassed by the invention are compounds of the formula:
Figure imgf000015_0003
and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted cycloalkyi, aryl, or heterocycle; X is a bond, -0-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)-
, -C(R4)=C(R4)-, -C≡C-, -N(Rs)-, -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-
, -ONC(R3)-, -C(R3)NO-, -C(R3R4)0-, -OC(R3R4)-, -S(02)-, -S(02)N(R5)-, -N(R5)S(02)-, -C(R3R4)S(02)-, or -S(02)C(R3R4)-; D is optionally substituted aryl or heterocycle; E is optionally substituted aryl or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; Rs is hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
Particular compounds are of the formula:
Figure imgf000016_0001
With regard to the formulae disclosed herein, particular compounds include those wherein A is optionally substituted cycloalkyi (e.g., 6-membered and 5-membered). In some, A is optionally substituted aryl (e.g., phenyl or naphthyl). In others, A is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, A is aromatic. In others, A is not aromatic. In some, A is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
Particular compounds are of the formula:
Figure imgf000016_0002
wherein: each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyi, aryl, or heterocycle. Compounds encompassed by this formula include those wherein Ai and/or A2 is optionally substituted cycloalkyi (e.g., 6-membered and 5-membered). In some, Ai and/or A2 is optionally substituted aryl (e.g., phenyl or naphthyl). In others, Ai and/or A2 is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, Ai and/or A2 is aromatic. In others, Ai and/or A2 is not aromatic.
With regard to the formulae disclosed herein, particular compounds include those wherein D is optionally substituted aryl (e.g., phenyl or naphthyl). In others, D is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, D is aromatic. In others, D is not aromatic. In some, D is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
With regard to the various formulae disclosed herein, particular compounds include those wherein E is optionally substituted aryl (e.g., phenyl or naphthyl). In others, E is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, E is aromatic. In others, E is not aromatic. In some, E is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
With regard to the various formulae disclosed herein, particular compounds include those wherein Ri is hydrogen or optionally substituted alkyi.
In some, R2 is hydrogen or optionally substituted alkyi.
In some, n is 1 or 2.
In some, X is a bond or S. In others, X is -C(R4)=, =C(R4)-, -C(R3R4)-, -C(R4)=C(R4)-, or -C≡C-, and, for example, R4 is independently hydrogen or optionally substituted alkyi. In others, X is -0-, -C(R3R4)0-, or -OC(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, and R4 is hydrogen or optionally substituted alkyi. In some, R3 is hydrogen and R4 is trifluoromethyl. In some compounds, X is -S(02)-, -S(02)N(R5)-, -N(R5)S(02)- , -C(R3R4)S(02)-, or -S(02)C(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, R4 is hydrogen or optionally substituted alkyi, and Rs is hydrogen or optionally substituted alkyi. In others, X is -N(R5)-, -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, or -N(R5)C(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyi, R4 is hydrogen or optionally substituted alkyi, and each Rs is independently hydrogen or optionally substituted alkyi.
Some compounds of the invention are encompassed by the formula:
Figure imgf000017_0001
wherein, for example, R3 is trifluoromethyl. Others are encompassed by the formula:
Figure imgf000017_0002
wherein, for example, R3 is hydrogen.
Some compounds are encompassed by the formula:
Figure imgf000018_0001
wherein: each of Zi, Z2, Z3, and Z4 is independently N or CR6; each R6 is independently hydrogen, cyano, halogen, OR7, NR8R9, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Re is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. Certain such compounds are of the formula:
Figure imgf000018_0002
Others are of the formula:
Figure imgf000018_0003
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000018_0004
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of Zi, Z2, Z3, and Z4 are N. In others, only three of Zi, Z2, Z3, and Z4 are N. In others, only two of Zi, Z2, Z3, and Z4 are N. In others, only one of Zi, Z2, Z3, and Z4 is N. In others, none of Zi, Z2, Z3, and Z4 are N.
Some compounds are of the formula:
Figure imgf000019_0001
wherein: each of ΖΊ, Z'2, and Z'3 is independently N, NH, S, 0 or CR6; each R6 is independently amino, cyano, halogen, hydrogen, OR7, SR7, NR8R9, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rs is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-3. Certain such compounds are of the formula:
Others are of the formula:
Figure imgf000019_0002
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000020_0001
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of ΖΊ, Z'2, and Z'3 are N or NH. In others, only two of ΖΊ, Z'2, and Z'3 are N or NH. In others, only one of ΖΊ, Z'2, and Z'3 is N or NH. In others, none of ΖΊ, Z'2, and Z'3 are N or NH.
Some compounds are encompassed by the formula:
Figure imgf000020_0002
wherein: each of Ζ'Ί, Zn2, Zn3, and Z"4 is independently N or CR10; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ru is independently hydrogen or optionally substituted alkyl, alkyl- aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
Figure imgf000020_0003
Figure imgf000021_0001
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000021_0002
Z"3, and Z"4 are N. In others, only three of Ζ'Ί, Z"2, Z' 3, and Z"4 are N. In others, only two of Z"i, Z"2, Z"3, and Z"4 are N. In others, only one of Ζ'Ί, Z"2, Z"3, and Z"4 is N. In others, none of Z"i, Z"2, Z"3, and Z" are N.
Some compounds are of the formula:
Figure imgf000021_0003
wherein: each of Ζ'Ί, Zn2, Zn3, and Z"4 is independently N or CR10; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ru is independently hydrogen or optionally substituted alkyl, alkyl- aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
Figure imgf000022_0001
Others are of the formula:
Figure imgf000022_0002
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000022_0003
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of Ζ'Ί, Z' 2, Z"3, and Z"4 are N. In others, only three of Ζ'Ί, Z"2, Z' 3, and Z"4 are N. In others, only two of Z"i, Z"2, Z"3, and Z"4 are N. In others, only one of Ζ'Ί, Z"2, Z"3, and Z"4 is N. In others, none of Z"i, Z"2, Z"3, and Z" are N.
Some are of the formula:
Figure imgf000022_0004
the substituents of which are defined herein.
Others are of the formula:
Figure imgf000023_0001
the substituents of which are defined herein.
Others are of the formula:
Figure imgf000023_0002
the substituents of which are defined herein.
Others are of the formula:
Figure imgf000023_0003
the substituents of which are defined herein.
Referring to the various formulae disclosed herein, particular compounds include those wherein both A and E are optionally substituted phenyl and, for example, X is -0-, -C(R3R4)0-, or -OC(R3R4)- and, for example, R3 is hydrogen and R4 is trifluoromethyl and, for example, n is 1.
Particular compounds of the invention are of formula III:
Figure imgf000023_0004
III
wherein: A2 is optionally substituted heterocycle; Ri is hydrogen, C(0)RA, C(0)ORA, or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; Rio is halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri4 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; RA is hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; RB is hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; Rc is hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. Some compounds are of the formula:
Some are
Figure imgf000024_0001
wherein: each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3.
Some compounds are of the formula:
Figure imgf000024_0002
wherein: each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-4. Others are of the formula:
Figure imgf000025_0001
wherein: each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and q is 1-2.
Some compounds are of the formula:
Figure imgf000025_0002
wherein: each R15 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and q is 1-2.
In particular compounds of formula III, A2 is aromatic. In others, A2 is not aromatic. In some, A2 is optionally substituted with one or more of halogen or lower alkyl. In some, R14 is hydrogen or halogen. In some, m is 1. In some, Rio is hydrogen or amino. In some, Ri is hydrogen or lower alkyl. In others, Ri is C(0)ORA and RA is alkyl. In some, R2 is hydrogen or lower alkyl. In some, R15 is hydrogen or lower alkyl (e.g., methyl). In some, n is i. In some, p is 1. In some, q is 1.
This invention encompasses stereomerically pure compounds and stereomerically enriched compositions of them. Stereoisomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns, chiral resolving agents, or enzymatic resolution. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
Particular compounds of the invention are potent TPHl inhibitors. Specific compounds have a TPHlJCso of less than about 10, 5, 2.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 μΜ.
Particular compounds are selective TPHl inhibitors. Specific compounds have a
TPHlJCso that is about 10, 25, 50, 100, 250, 500, or 1000 times less than their TPH2_ICso.
Specific THP1 inhibitors include:
(S)-2-amino-3-(4-(5-(2-fluoro-4,5-dimethoxybenzylamino)pyrazin-2-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(4-(2-methoxyphenyl)piperidin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)-2- (dimethylamino)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(5-(3,4-dimethylbenzylamino)pyrazin-2-yl)phenyl)propanoic acid; (S)-2-amino-3-(4-(5-(biphenyl-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid;
(S)-ethyl 2-amino-3-(4-(2-amino-6-(4-(trifluoromethyl)benzylamino)pyrimidin-4- yl)phenyl)propanoate;
(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate;
(S)-2-amino-3-(4-(5-(cyclopentylmethylamino)pyrazin-2-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(3-(2-(trifluoromethyl)phenyl)pyrrolidin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l,2,3,4-tetrahydronaphthalen-l-ylamino)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-l-(naphthalen-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l,2-diphenylethylamino)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-(benzo[b]thiophen-3- yl)phenyl)ethylamino)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(4-amino-6-((R)-l-(4'-methoxybiphenyl-4-yl)ethylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
2-amino-3-(l-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2-yl)piperidin- 4-yl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(l-(4-fluoronaphthalen-l-yl)ethylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid; (S)-2-amino-3-(4-(4-amino-6-((3'-fluorobiphenyl-4-yl)methylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
2-amino-3-(4-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2-yl)-2- fluorophenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-2-yl)ethoxy)-l,3,5- triazin-2-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(l-(44ert-butylphenyl)ethylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(3'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(6 -dihydroxy-l-methyl-3,4-dihydroisoquinolin-2(lH)-yl)- l,3,5-triazin-2-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l-(3'-methylbiphenyl-4-yl)ethoxy)-l,3,5- triazin-2-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)pyrimidin-2- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(4'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(3-(4-chlorophenoxy)piperidin-l-yl)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-3-(4-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2-yl)phenyl)-2-(2- aminoacetamido)propanoic acid;
(S)-2-amino-3-(4-(6-((R)-l-(naphthalen-2-yl)ethylamino)-2-(trifluoromethyl)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(4-(3-chlorophenyl)piperazin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-phenylethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l,4-diphenylbutylamino)pyrimidin-4-yl)phenyl)propanoi acid;
(2S)-2-amino-3-(4-(6-(l-(3'-chlorobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(4-amino-6-(l-(biphenyl-4-yl)-2,2,2-trifluoroethoxy)-l,3,5-triazin-2- yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(2,2,3,3,3-pentafluoro-l-(3-fluoro-4- methylphenyl)propoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;
(S)-2-amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3-fluoro-3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(3'-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-methoxy-5-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4'-methoxy-5-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-methoxy-3-(methylsulfonyl)biphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(isopentyloxy)phenyl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-4-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4'-methoxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(3'-carbamoylbiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4'-carbamoylbiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(2- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(2-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(2-(isopentyloxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-3-(4-(6-(l-(3'-acetamidobiphenyl-2-yl)-2,2,24rifluoroethoxy)-2-aminopyrimidin-4- yl)phenyl)-2-aminopropanoic acid; (2S)-3-(4-(6-(l-(4'-acetamidobiphenyl-2-yl)-2,2,24rifluoroethoxy)-2-aminopyrimidin-4- yl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-cyanophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-p-tolylethoxy)pyrimidin-4- yl)phenyl)propanoate;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-methoxybicyclo[2.2.2]oct-5-en-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-(cyclopentyloxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(4-(cyclopentyloxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(3- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4,5-dimethoxybiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4,5-dimethoxy-3'-methylbiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(2'-methylbiphenyl-2-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(3-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(3,5-difluorophenoxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(4- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4'-((S)-2-amino-2-carboxyethyl)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(3'-methylbiphenyl-2-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-methoxybiphenyl-2-yl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(2-(4-methylthiophen-3-yl)phenyl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-methoxy-3'-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-(hydroxymethyl)biphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(3'-cyanobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(3,5-difluorophenoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(4-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(4-methylthiazol-2-yl)thiophen-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(5-(4-methoxyphenyl)isoxazol-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-phenyl-5-(trifluoromethyl)-lH-pyrazol-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(benzo[d]thiazol-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-methyl-lH-imidazol-5- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(pyridin-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(l,3-dimethyl-lH-pyrazol-5-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(3-hydroxyphenyl)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(3'-hydroxybiphenyl-2-yl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(3,5-difluorophenyl)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(l-(3',5'-difluorobiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-3-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(l-(5-ethoxy-2-methyl-2,3-dihydrobenzofuran-6-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(benzofuran-5-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(2-m-tolylfuran-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-ethyl 3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin- 4-yl)phenyl)-2-(2-aminoacetamido)propanoate;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(2-(4-methylthiophen-3-yl)phenyl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(5-methyl-3-phenylisoxazol-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(3-(methylthio)phenyl)pyrimidin-4-yl)phenyl)propanoi acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-(methylthio)biphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(3H(dimethylamino)methyl)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-(trifluoromethoxy)biphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)-2-(2-aminoacetamido)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-methyl-5-phenyl-lH-pyrazol-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4- (methylsulfonyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-l-(3'-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-chloro-4-(methylsulfonyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3-(furan-2-yl)thiophen-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(3-methoxyphenyl)cyclohex-l- enyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(pyrimidin-5-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(3'-methoxybiphenyl-3-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((S)-l-(3'-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(furan-2- carboxamido)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-chloro-2-(methylsulfonyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-isopropyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;
(2S)-2-amino-3-(4-(6-(l-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-(thiophen-2- yl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-(2,2,2-trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)thiazol-5- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-(4- methoxyphenyl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-fluoro-2-methylphenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-fluoro-2- methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(oxazol-2-yl(phenyl)methoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(l-cyclohexyl-2,2,24rifluoroethylideneaminooxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(3-(dimethylamino)phenyl)furan-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(5^henylthiophen-2-yl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(S)-phenyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate; (S)-2-amino-3-(4-(2-amino-6-((R)-l-(3H(dimethylamino)methyl)biphenyl-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(l-(3-methoxybenzoyl)-lH-pyrazol-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(5-phenylfuran-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-(2-amino-6-(4-(trifluoromethyl)styryl)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-l-(3'-(dimethylamino)biphenyl-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-chloro-2,2,2-trifluoro-l-(4-methoxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(5-phenylthiophen-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(5-(4-phenoxyphenyl)-lH-l,2,3-triazol-l-yl)phenyl)propanoic acid;
(S,E)-2-amino-3-(4-(2-amino-6-(2-(biphenyl-4-yl)vinyl)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(4-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-2-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(4'-methoxybiphenyl-4-ylsulfonamido)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(3-methoxyphenyl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(2-fluoro-3-methoxyphenyl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
2-amino-3-(5-(4'-methylbiphenyl-4-yl)-lH-indol-3-yl)propanoic acid;
2-amino-3-(5-m-tolyl-lH-indol-3-yl)propanoic acid;
(2S)-2-amino-3-(4-(2-(2-methoxyphenyl)furan-3-carboxamido)phenyl)propanoic acid; 2-amino-3-(5-(l-benzyl-lH-pyrazol-4-yl)-lH-indol-3-yl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(thiophen-2-yl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
2-amino-3-(6-(l-benzyl-lH-pyrazol-4-yl)-lH-indol-3-yl)propanoic acid;
(S)-2-amino-3-(4-((2-(4-(trifluoromethyl)phenyl)thiazol-4- yl)methylamino)phenyl)propanoic acid; (S)-2-amino-3-(4-((4'-methoxybiphenyl-4-ylsulfonamido)methyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(3-(2-methoxydibenzo[b,d]furan-3-yl)ureido)phenyl)propanoic acid;
(S)-2-amino-3-(4-(3-(2,2-diphenylethyl)ureido)phenyl)propanoic acid;
(S)-2-amino-3-(4-(phenylethynyl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((5-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)thiophen-2- yl)methoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l,l,l-trifluoro-3-((R)-2,2,3-trimethylcyclopent-3- enyl)propan-2-yloxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(3-(2-hydroxyethylcarbamoyl)piperidin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(3-(pyridin-2-yloxy)piperidin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(4-chloro-3-(piperidine-l-carbonyl)phenyl)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(pyridin-3-yl)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(2-methylpyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(4-methylthiophen-3- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-3-(4-(6-(l-(2-(lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4- yl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(4-(furan-2-yl)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(2-(pyridin-3-yloxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-3-(4-(6-(l-(2-(lH-l,2,44riazol-l-yl)phenyl)-2,2,24rifluoroethoxy)-2-aminopyrimidin-4- yl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,24rifluoro-l-(2-(furan-3-yl)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(furan-2-yl)-3- methoxyphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-l-(2-(furan-2-yl)phenyl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-3-(4-(5-(l-(2-(lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)-2- aminopropanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4,5-dimethoxy-2-(lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(2-methyl-lH-imidazol-l- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(5-methylthiophen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(2-(5-(dimethylcarbamoyl)furan-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-fluoro-2-(thiophen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-fluoro-2-(thiophen-2-yl)phenyl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-fluoro-2-(thiophen-3-yl)phenyl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-fluoro-2-(4-methylthiophen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(6-fluoropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-3-(4-(6-(l-(4-(lH-imidazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4- yl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(thiophen-2-yl)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(6-(l-(2-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(2-methylpyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-3-(4-(6-(l-(4-(lH-l,2,4-triazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)-2-aminopropanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-(piperidin-l- ylmethyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-fluoro-4-(2-methylpyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-(6-chloropyridazin-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(l-(4-(4-tert-butylthiazol-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-methoxy-3-(3-methyl-lH-pyrazol-l- yl)biphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; and (2S)-2-amino-3-(4-(2-amino-6-(l-(5-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
Particular THP1 inhibitors are: (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'- methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-ethyl 2-amino-3-(4-(2- amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoate; and (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid, and pharmaceutically acceptable salts thereof.
When administered to mammals (e.g., mice, rats, dogs, monkeys or humans), certain compounds of the invention do not readily cross the blood/brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or 0.01 percent of compound in the blood passes into the brain). The ability or inability of a compound to cross the blood/brain barrier can be determined by methods known in the art. See, e.g., Riant, P. et al., Journal of Neurochemistrv 51:421-425 (1988); Kastin, A.J., Akerstrom, V., J. Pharmacol. Exp. Therapeutics 294:633-636 (2000); W. A. Banks, W.A., et al., J. Pharmacol. Exp. Therapeutics 302:1062-1069 (2002).
5.3. Pharmaceutical Compositions
Pharmaceutical compositions comprising one or more of the TPH1 inhibitors described herein are provided. Certain pharmaceutical compositions are single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or nonaqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
The formulation should suit the mode of administration. For example, the oral administration of a compound susceptible to degradation in the stomach may be achieved using an enteric coating. Similarly, a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action. For example, compounds may be administered in liposomal formulations in order to protect them from degradative enzymes, facilitate transport in circulatory system, and effect their delivery across cell membranes.
Similarly, poorly soluble compounds may be incorporated into liquid dosage forms (and dosage forms suitable for reconstitution) with the aid of solubilizing agents, emulsifiers and surfactants such as, but not limited to, cyclodextrins (e.g., a-cyclodextrin, β-cyclodextrin, Captisol®, and Encapsin™ (see, e.g., Davis and Brewster. Nat. Rev. Drug Disc. 3:1023-1034 (2004)), Labrasol®, Labrafil®, Labrafac®, cremafor, and non-aqueous solvents, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide
(DMSO), biocompatible oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof (e.g., DMSO:cornoil).
Poorly soluble compounds may also be incorporated into suspensions using other techniques known in the art. For example, nanoparticles of a compound may be suspended in a liquid to provide a nanosuspension (see, e.g., Rabinow, Nature Rev. Drug Disc. 3:785-796 (2004)). Nanoparticle forms of compounds described herein may be prepared by the methods described in U.S. Patent Publication Nos. 2004-0164194, 2004-0195413, 2004-0251332, 2005-0042177 Al, 2005-0031691 Al, and U.S. Patent Nos. 5,145,684, 5,510,118,
5,518,187, 5,534,270, 5,543,133, 5,662,883, 5,665,331, 5,718,388, 5,718,919, 5,834,025, 5,862,999, 6,431,478, 6,742,734, 6,745,962, the entireties of each of which are incorporated herein by reference. In one embodiment, the nanoparticle form comprises particles having an average particle size of less than about 2000 nm, less than about 1000 nm, or less than about 500 nm.
The composition, shape, and type of a dosage form will typically vary depending with use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. How to account for such differences will be apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
5.3.1. Oral Dosage Forms
Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by conventional methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets).
5.3.2. Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include: Water for Injection USP; aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
5.4. Methods
This invention encompasses methods of treating IBS patients who are more likely to respond to TPH inhibitor therapy. Applicants have discovered that for non-constipating IBS, patients that are genotype AA or AC at SNP rs7130929 and/or are genotype CC or CT at SNP rs4537731 are more likely to respond to TPH inhibitory therapy. Response can be measured by global relief of symptoms or by stool consistency. In some embodiments, methods of treating, managing and/or preventing irritable bowel syndrome (IBS), including diarrhea-predominant IBS (IBS-D) and mixed IBS (IBS-A), comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, methods of treating, managing and/or preventing irritable bowel syndrome (IBS), including diarrhea-predominant IBS (IBS-D) and mixed IBS (IBS-A), comprise
administering to a patient in need thereof a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. Exemplary TPH inhibitors are the compounds disclosed herein.
Some embodiments encompass a method of treating or managing irritable bowel syndrome (IBS), which comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has been determined to be genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the patient suffering from IBS has been determined to have a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, if a patient suffering from IBS, such as non-constipating IBS, diarrhea-predominant IBS (IBS-D), and mixed IBS (IBS- A), has been determined to be genotype CC at SNP rs7130929 and/or genotype TT at SNP rs4537731, the patient is not recommended for TPH inhibitor therapy. In some embodiments, if a patient suffering from IBS, such as non-constipating IBS, diarrhea-predominant IBS (IBS-D), and mixed IBS (IBS-A), has been determined to have a genotype that is closely linked to genotype CC at SNP rs7130929 and/or genotype TT at SNP rs4537731, the patient is not recommended for TPH inhibitor therapy. The genotype of the patient at a TPH SNP, such as SNP rs7130929 or SNP rs4537731, may be determined by any method.
In some embodiments, methods of treating and/or managing IBS comprise administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has been determined to be genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731. In some
embodiments, the patient suffering from IBS has been determined to have a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731. In some embodiments, the patient is suffering from non-constipating IBS, such as IBS-D or IBS-A. In some embodiments, the patient is suffering from diarrhea-predominant IBS (IBS-D).
In some embodiments, the TPH inhibitor is administered orally. In some, the TPH inhibitor is administered twice (BID) or three times (TID) daily.
In some embodiments, methods of determining whether a patient will respond to treatment with a TPH inhibitor are provided. In some such embodiments, the method comprises determining the patient's genotype at a TPH SNP. In some such embodiments, the method comprises determining the patient's genotype at SNP rs7130929 and/or at SNP rs4537731. In some embodiments, genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731, or a genotype at a TPH SNP that is closely linked to one of those genotypes, indicates that the patient may respond to treatment with a TPH inhibitor. In some embodiments, genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731, or a genotype at a TPH SNP that is closely linked to one of those genotypes, indicates that the patient may respond to treatment with a TPH inhibitor. In some embodiments, a patient is considered to respond to treatment with a TPH inhibitor when the patient's symptoms improve or do not worsen.
In some embodiments, a method of determining if a patient suffering from IBS will be responsive to TPH inhibitor therapy is provided, which comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of: improvement with defecation, onset associated with a change in frequency of stool, or onset associated with a change in form (appearance) of stool; and b) if the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from IBS will be responsive to TPH inhibitor therapy is provided, which comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of: improvement with defecation, onset associated with a change in frequency of stool, or onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy is provided, which comprises determining if the patient is genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient is genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
In some embodiments, a method of determining if a patient suffering from non- constipating IBS will respond to TPH inhibitor therapy is provided, which comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA or AC at SNP rs7130929 and/or genotype CC or CT at SNP rs4537731. In some embodiments, the method comprises determining if the patient has a genotype at a TPH SNP that is closely linked to genotype AA at SNP rs7130929 and/or genotype CC at SNP rs4537731.
In any of the embodiments herein, the IBS may be non-constipating IBS, diarrhea- predominant IBS (IBS-D), or mixed IBS (IBS-A).
5.4.1. Genotype Detection
The genotype of a patient at SNP rs7130929 and/or SNP rs4537731 and/or another TPH SNP may be determined using any of a variety of nucleic acid techniques known, including but not limited to, nucleic acid sequencing and genotyping by various methods, including hybridization-based genotyping methods, enzyme-based genotyping methods, and genotyping methods based on physical properties of DNA. Any suitable method of sequencing nucleic acids may be used to determine the genotype of a patient. Non-limiting examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing, dye terminator sequencing, pyrosequencing, sequencing-by-ligation, single molecule sequencing, single-base addition sequencing, sequence-by-synthesis (SBS), massive parallel clonal, massive parallel single molecule SBS, massive parallel single molecule real-time, massive parallel single molecule real-time nanopore technology, DNA nanoball sequencing, ion semiconductor sequencing, etc. See, e.g., Sanger et al., Proc. Natl. Acad. Sci. USA 74:5463-5467 (1997); Maxam et al., Proc. Natl. Acad. Sci. USA 74:560-564 (1977); Drmanac, et al., Nat. Biotechnol. 16:54-58 (1998); Kato, Int. J. Clin. Exp. Med. 2:193-202 (2009); Ronaghi et al., Anal. Biochem. 242:84-89 (1996); Margulies et al., Nature 437:376-380 (2005); Ruparel et al., Proc. Natl. Acad. Sci. USA
102:5932-5937 (2005), and Harris et al., Science 320:106-109 (2008); Bennett et al., Pharmacogenomics, 6: 373-382 (2005); Levene et al., Science 299:682-686 (2003); Korlach et al., Proc. Natl. Acad. Sci. USA 105:1176-1181 (2008); Branton et al., Nat. Biotechnol.
26(10):1146-53 (2008); Eid et al., Science 323:133-138 (2009); Morozova et al., Genomics, 92: 255 (2008); Mitra et al., Analytical Biochemistry 320: 55-65 (2003); Shendure et al., Science 309: 1728-1732 (2005); Margulies et al., Nature 437: 376-380 (2005); Bennett et al.,
Pharmacogenomics, 6: 373-382 (2005); Brenner et al. Nat. Biotechnol. 18:630-634 (2000); Adessi et al. Nucleic Acid Res. 28: E87 (2000); Voelkerding et al., Clinical Chem., 55: 641-658 (2009); MacLean et al., Nature Rev. Microbiol., 7: 287-296; Astier et al., J. Am. Chem. Soc.
128(5):1705-10 (2006); Porreca, Nature Biotech. 28(1): 43-44 (2010); Rusk, Nature Methods, 8(1): 44 (2011); U.S. Patent Nos. 6,432,360; 6,485,944; 6,511,803; 6,787,308; 6,833,246; 5,695,934; 5,714,330; 7,169,560; 7,282,337; 7,482,120; 7,501,245; 6,818,395; 6,911,345; and 7,501,245.
Any suitable method of genotyping may be used to determine the genotype at SNPs rs7130929 and rs4537731. Nonlimiting exemplary genotyping methods are reviewed, for example, in Kwok et al., Curr. Issues Mol. Biol. 5: 43-60 (2003); and Kim et al., Ann. Rev.
Biomed. Engineering 9: 289-320 (2007). Hybridization-based genotyping methods include, but are not limited to, dynamic allele-specific hybridization (DASH), which detects a genotype based on differences in melting temperature that result from mismatched base pairs; molecular beacons, which use hairpins comprising a dye and a quencher that will fluoresce only in the presence of a target sequence (such as a particular genotype); single-nucleotide polymorphism microarrays; and Southern blotting. See, e.g., Howell et al., Nature Biotechnology, 17: 87-8 (1999); Abravaya et al., Clin Chem Lab Med. 41:468-474 (2003); and Rapley and Harbron, Molecular Analysis and Genome Discovery. Chichester. John Wiley & Sons Ltd. (2004).
Enzyme-based genotyping methods include, but are not limited to, restriction fragment length polymorphism, in which the presence of SNPs result in different restriction digest patterns; PCR-based genotyping, using, for example, SNP-specific primers; flap endonuclease (FEN)-based methods (such as the Invader® assay and Serial Invasive Signal Amplification Reaction (SISAR) assay), in which a SNP-specific tripartite structure is formed and cleaved by FEN; primer extension-based genotyping (such as the Infinium® assay, APEX assay, and APEX-2 assay), in which a primer is hybridized near the SNP and a single-base extension reaction, in some instances with a labeled nucleoside, is used to determine the genotype; mass spectrometer-based assays (such as iPLEX SNP genotyping assay, Sequenom), in which the identity of the single base addition is determined by mass spectrometry rather than a detectable label; 5'-nuclease-based methods (such as TaqMan® assays), in which allele-specific TaqMan® probes are used to distinguish SNPs; and oligonucleotide ligase-based assays (OLA), in which a first probe is ligated to a second probe only in the presence of a particular allele.
See, e.g., Olivier, Mutat Res. 573(1-2):103-10 (2005); Rao et al., Nucleic Acids Res. 31(ll):e66 (2003); Rapley R., Harbron S. (Eds.) Molecular Analysis and Genome Discovery. Chichester. John Wiley & Sons Ltd. (2004); Gunderson et al., Methods Enzymol. 410:359-76 (2006); Krjutskov et al., Nucl. Acids Res. 36: e75 (2008); McGuigan et al., Psychiatr Genet. 12(3):133-6 (2002); and Syvanen, Nat Rev Genet. 2(12):930-42 (2001).
Genotyping methods based on physical properties of DNA, which are typically carried out after amplification of a region containing the SNP, include, but are not limited to, single- strand conformation polymorphism, in which SNP-dependent differences in the tertiary folding of a single-stranded DNA are detected; temperature gradient gel electrophoresis, in which SNPs are detected based on differences in the rate that a double-stranded DNA travels when it comprises a mismatch; denaturing high-performance liquid chromatography, in which differences in melting temperatures are detected by retention time in the column; high- resolution melting of an amplicon, in which differences in melting temperature of a DNA amplicon are detected; and SNPlex (Life Technologies, Carlsbad, CA). See, e.g., Costabile et al., Hum Mutat. 27(12):1163-73(2006); Rapley and Harbron, Molecular Analysis and Genome
Discovery. Chichester. John Wiley & Sons Ltd. (2004); Oefner et al., Am J Hum Genet. 57, A266 (1995); Gundry et al., Clin Chem. 49(3):396-406 (2003); and Tobler et al., Journal of
Biomolecular Techniques 16 (4): 398-406 (2005).
In various embodiments at least one region of the genome comprising SNP rs7130929 and/or SNP rs4537731 is amplified. In some embodiments, at least one region is amplified prior to sequencing and/or SNP detection. Any suitable method of amplification may be used. Nonlimiting exemplary methods of nucleic acid amplification include the polymerase chain reaction (PCR), transcription mediated amplification (TMA), ligase chain reaction (LCR), strand- displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). See, e.g., Mullis et al., Meth. Enzymol. 155: 335 (1987); Murakawa et al., DNA 7: 287 (1988); U.S. Patent Nos. 5,480,784 and 5,399,491; Weiss, R., Science 254: 1292 (1991); Walker, G. et al., Proc. Natl. Acad. Sci. USA 89: 392-396 (1992); and U.S. Patent No. 5,130,238. 5.4.2. Bioinformatics
In some embodiments, a computer-based analysis program is used to translate the raw data generated by the detection assay (e.g., the identity, presence, or absence of a particular allele at rs7130929 and/or rs4537731 and/or at another TPH SNP) into data of predictive value for a clinician. The clinician can access the predictive data using any suitable means. Thus, in some preferred embodiments, the present invention provides the further benefit that the clinician, who may not be trained in genetics or molecular biology, need not understand the raw data. The data is presented directly to the clinician in its most useful form. The clinician is then able to immediately utilize the information in order to optimize the care of the patient.
Any method capable of receiving, processing, and transmitting the information to and from laboratories conducting the assays, information providers, medical personal, and patients is contemplated. For example, in some embodiments, a sample (such as a blood sample) is obtained from a patient and submitted to a profiling service (e.g., clinical lab at a medical facility, genomic profiling business, etc.), located in any part of the world (e.g., in a country different than the country where the patient resides, where the sample is obtained from the patient, or where the information is ultimately used) to generate raw data. Where the sample comprises a tissue or other biological sample, the patient may visit a medical center to have the sample obtained and sent to the profiling center, or, in some instances, patients may collect the sample themselves (e.g., a urine or fecal sample) and directly send it to a profiling center. Once received by the profiling service, the sample is processed and a profile is produced (e.g., the identity, presence, or absence of a particular allele at rs7130929 and/or rs4537731 and/or at another TPH SNP).
In some embodiments, the profile data is then prepared in a format suitable for interpretation by a treating clinician. For example, rather than providing raw data, in some embodiments, the prepared format may represent a diagnosis or risk assessment for the patient (e.g., an indication that the patient is more likely, or less likely, to respond to treatment with TPH inhibitor), along with recommendations for particular treatment options. The data may be displayed to the clinician by any suitable method. For example, in some embodiments, the profiling service generates a report that can be printed for the clinician (e.g., at the point of care) or displayed to the clinician on a computer monitor. In some embodiments, the raw data is provided to the point of care facility or other regional facility. In some such embodiments, the receiving facility further analyzes and/or converts the raw data to information useful for a clinician or patient.
In some embodiments, the patient is able to directly access the data using the electronic communication system. The patient may chose further intervention or counseling based on the results. In some embodiments, the data is used for research use. For example, the data may be used to further optimize the inclusion or elimination of markers as useful indicators of a particular condition or stage of disease, or as a predictor of response to treatment.
It is to be understood that the data analysis and transmission may be implemented in various forms of hardware, software, firmware, processors, distributed servers (e.g., as used in cloud computing) or a combination thereof. The methods and systems described herein can be implemented as a combination of hardware and software. The software can be implemented as an application program tangibly embodied on a program storage device, or different portions of the software implemented in the user's computing environment (e.g., as an applet) and on the reviewer's computing environment, where the reviewer may be located at a remote site (e.g., at a service provider's facility). For transmissions, in some embodiments, part or all of the input and output data can be sent electronically or telephonically (e.g., by facsimile, e.g., using devices such as fax back). In some embodiments, all or a portion of the input data and/or all or a portion of the output data are maintained on a server for access, e.g., confidential access. The results may be accessed or sent to professionals as desired.
In some embodiments, kits are provided for determining whether a patient suffering from IBS will be responsive to TPH inhibitor therapy, which comprise reagents for determining a patient's genotype at SNP rs7130929 and/or at SNP rs4537731 and/or at another TPH SNP. Such kits may include primers, controls, enzymes, buffers, and the like.
6. EXAMPLES 6.1. Treatment of IBS Patients Using (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-
(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid
A randomized, double-blind, placebo-controlled phase 2a clinical trial was conducted to assess the safety and efficacy of a TPH inhibitor, (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro- l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, in 155 patients suffering from IBS-D or IBS-A, based on Rome III criteria. Capsules containing the compound or placebo were orally administered. Two dose levels were tested: 250 mg QID and 1000 mg QID. A two-week run-in period was used to establish baseline symptoms, followed by a 28 day randomized, double-blind treatment period. There was then a two-week follow-up period.
During the study, patients' urine and blood were obtained. Methods used to assess clinical endpoints were: 1) global assessment by weekly questioning regarding adequate relief of IBS pain and discomfort; and 2) Bristol Stool Scale was used to assess stool consistency by daily automated telephonic IVRS contact.
It was found that patients randomized to the high dose arm showed a statistically significant improvement versus placebo in the weekly global assessment. The patients also showed significant improvement in stool consistency. 6.2. TPHl Promoter Genotype of Responders and Non-responders
The TPHl promoter contains the SNPs rs7130929 and rs4537731. Figure 1 shows a portion of the 5' untranslated region of the TPHl gene with the location of the SNPs indicated.
The CC genotype at rs7130929 in the TPHl promoter correlates with higher expression of TPHl. The AA genotype at rs7130929 in the TPHl promoter correlates with lower expression of TPHl, while the CA genotype correlates with intermediate expression. Similarly, at the rs4537731 SNP in the TPHl promoter, which is linked to the rs7130929 SNP, the TT genotype correlates with higher expression of TPHl, the CC genotype correlates with lower expression of TPHl, and the CT genotype correlates with intermediate expression. See, e.g., Sun et al., Alcohol Clin Exp Res, 29(1): 1-7 (2005); Rotondo et al., Mol. Psychiatry, 4(4): 360-368 (1999). It has also been found that the higher expressing alleles of TPHl (i.e., the CC genotype at rs7130929 and the TT genotype at rs4537731) correlate with IBS-D. See, e.g., Grasberger et al., Gastroenterology, 140(5): Sill. Accordingly, it would have been predicted that the CC genotype at rs7130929 and the TT genotype at rs4537731 would also be markers for response to TPH inhibitors, such as (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl- 4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, which are effective in IBS-D.
To test the correlation, one hundred and five blood samples from the phase 2a clinical trial were genotyped at the rs7130929 and rs4357731 SNPs located in the TPHl promoter, as follows.
Genomic DNA extraction
Five μΙ of whole blood was swelled in 1ml of MilliQ water at room temperature for 30 minutes. The mixture was centrifuged at 3000 rpm for 5 minutes in a Beckman Centrifuge SK6 centrifuge. All but 20-30 μΙ of the supernatant was removed. 150 μΙ of 6% InstaGene matrix (BioRad 142-1253) was added and the mixture was vortexed to resuspend the pellet. The mixture was incubated at 65°C for 30 minutes. The sample was vortexed at maximum speed for 10 seconds, and then incubated in a 100°C sand box for 8 minutes. Each sample was vortexed again at maximum speed for 10 seconds, followed by centrifugation at 3000 rpm for 5 minutes. The supernatant (150 μΙ) was transferred to a 96-well v-bottom plate and stored at - 80°C. The average expected concentration of genomic DNA in the supernatant was -30 ng/μΙ.
Rs7130929 genotyping
PCR was performed with Kapa 2G Fast DNA polymerase (KAPA Biosystems KK5021) according to manufacturer's instructions using primers 5'- TTGGGATAAGGAGCTAATCGACTGA-3' (SEQ ID NO: 1) and 5'-TGCGTGTATCTGACTGGTG-3' (SEQ ID NO: 2). Briefly, -lOOng of genomic DNA template was used for each 25μΙ reaction containing lx reaction buffer, 0.2mM dNTPs, 3 mM MgC , 0.5μΜ primers, and 0.5 Units of KSPA2G Fast DNA polymerase. Reactions were cycled as follows: Denature at 95°C for 2 minutes followed by 35 cycles of 95°C for 20 seconds, 60°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute. Reaction products were purified by passing through Sephacryl- 300-HR (Sigma S300HR) and Sephadex G-50 (GE Health 17-0042-02) columns. A total of 2 μΙ purified DNA was used for Sanger sequencing with the same primers used for PCR.
As verification of the original results, PCR was repeated on all samples using iProof High fidelity DNA polymerase (Bio-Rad 172-5301) according to manufacturer's instructions using the same primers used above. Briefly, -100 ng of genomic DNA was used for each 20 μΙ reaction containing lx iProof HF buffer, 0.2 mM dNTPs, 0.5 μΜ primers, and 0.5 Units iProof high fidelity DNA polymerase. Reactions were cycled as follows: Denature at 98°C for 2 minutes followed by 35 cycles of 98°C for 15 seconds, 61°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute. Reaction products were purified by first adding 10 μΙ of H2O followed by passing through Sephacryl-300 and Sephadex G-50 columns. A total of 2 μΙ purified DNA was used for Sanger sequencing with nested primers 5'- ATAAG G AGCTAATCG ACTG ACTACT-3 ' (SEQ ID NO: 3) and 5'-CTAACACTGAACAATCCAGA-3' (SEQ ID NO: 4).
Rs4357731 genotyping
PCR was performed using Kapa2G Fast DNA polymerase and primers 5'-
TTATG GCATTG AAGTAAG AGCAC-3 ' (SEQ ID NO: 5) and 5 '-G GTATTTACTG GTTG AGTAGTC-3 ' (SEQ ID NO: 6). Briefly, -100 ng of genomic DNA template was used for each 25 μΙ reaction containing lx reaction buffer, 0.2 mM dNTPs, 3 mM MgCb, 0.5 μΜ primers, and 0.5 Units of KAPA2G Fast DNA polymerase. Reactions were cycled as follows: Denature at 95°C for 2 minutes followed by 35 cycles of 95°C for 20 seconds, 57°C for 15 seconds, and 72°C for 30 seconds, followed by a 72°C hold for 1 minute and a 4°C hold for 1 minute. Reaction products were purified by passing through Sephacryl-300-HR (Sigma S300HR) and Sephadex G-50 (GE Health 17-0042-02) columns. A total of 2 μΙ purified DNA was used for Sanger sequencing with the same primers used for PCR.
Combined assay for genotyping rs7130929 and rs4537731
Representative samples are selected. Two rounds of PCRs are performed using iProof High fidelity DNA polymerase (Bio-Rad 172-5301) and primers 5'-
TTATGGCATTGAAGTAAGAGCAC-3 (SEQ ID NO: 5) and 5'-TGCGTGTATCTG ACTG GTG-3 ' (SEQ ID NO: 2) according to the reaction conditions described for rs7130929, except that the annealing temperature is increased to 61°C. Nested primers 5'-GCATTGAAGTAAGAGCACTGGAT-3' (SEQ ID NO: 7) and 5'-GTG AATGTTAG GCCGTCCTTAACCA-3 ' (SEQ ID NO: 8) are employed in the 2nd round of PCR. PCR products are cleaned by passing through Sephacryl-300 and Sephadex G-50 columns then cloned with Zero Blunt Topo blunt PCR cloning kit (Invitrogen K287540). Cloned products are sequenced using the T7 primer 5'-TAATACGACTCACTATAGGG-3' (SEQ ID NO: 9) present in the vector. In some embodiments, this method resolves the discrepancy discussed below between PCR and SNP analysis for some samples. In some embodiments, the discrepancy may be due to a SNP in certain samples affecting the annealing efficiency of certain commercial primers. Sequencing
Sequencing reactions were prepared in 10 μί volume with 0.5 μί of BigDye Terminator vl.l premix (Applied Biosystems) in lx reaction buffer and 3.2 pmol primer. Reactions were cycled as follows: Denature at 94°C for 3 minutes followed by 36 cycles of 94°C for 35 seconds, 52°C for 25 seconds, and 60°C for 2 minutes, followed by a 60°C hold for 3 minutes and a 4°C hold for 1 minute. Unincorporated dye terminators were removed from completed reactions by first adding 15 μΙ of H2O followed by passing through Sephadex G-50 columns. After addition of EDTA to a final concentration of 0.2 mM, the purified products were subjected to DNA Analyzer ABI Prism 3730x1 (Applied Biosystems).
SNPs analysis
SNP reactions were prepared using SNP Genotyping Assay kits from ABI
(C_2645686_10 and C_2645685_10 for rs4531137 and rs7130929 respectively) at 6 μΙ total volume. ~1 to 10 ng of genomic DNA was used for the assay. Cycled- PCRs were run as follows: 50°C for 2 minutes, 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 1 minute for rs4531137 or 62°C for 1 minute for rs7130929. Allelic Analysis was run on ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Data were collected both before and after cycled-PCR.
Results
The results of the genotyping for rs7130929 for each sample, as determined by sequencing and by SNP are shown in Table 1. Each sample was sequenced twice and subjected to SNP analysis twice, except for six samples that failed to sequence the second time.
Table 1: rs7130929 genotype
Figure imgf000047_0001
Sample # Sequencing 1 Sequencing 2 SNP Analysis 1 SNP Analysis 2
23 AC No Data AC AC
24 CC CC CC CC
25 CC CC CC CC
26 AA AA AA AA
27 AC AC AC AC
28 AC AC AC AC
29 AA AA AA AA
30 AC AC CC CC
31 CC CC CC CC
32 AC AC AC AC
33 AA No Data AA AA
34 CC No Data CC CC
35 CC CC CC CC
36 CC CC CC CC
37 AC AC AC AC
38 AA AA AA AA
39 AC AC AC AC
40 AC AC AC AC
41 AA AA AA AA
42 AC AC AC AC
43 CC CC CC CC
44 AA AA AA AA
45 AC AC AC AC
46 AC AC AC AC
47 CC CC CC CC
48 AC AC AC AC
49 AC AC AC AC
50 AC AC AC AC
51 AC AC AC AC
52 AA AA AA AA
53 AC AC AC AC
54 AC AC AC AC
55 AA AA AA AA
56 AC AC AC AC
57 CC CC CC CC
58 AA AA AA AA
59 AA AA AA AA
60 AC AC AC AC
61 AC AC AC AC
62 AC AC AC AC
63 AC AC AC AC
64 CC CC CC CC
65 AC AC AC AC
66 AC AC AC AC
67 AC AC AC AC
68 AA AA AA AA
69 AC AC AC AC
70 AA AA AA AA
71 AC AC AC AC
72 AC AC AC AC
73 CC CC CC CC
74 CC CC CC CC
75 CC No Data CC CC Sample # Sequencing 1 Sequencing 2 SNP Analysis 1 SNP Analysis 2
76 AC AC AC AC
77 CC CC CC CC
78 CC CC CC CC
79 CC CC CC CC
80 AC AC AC AC
81 AC No Data AC AC
82 AC AC AC AC
83 CC CC CC CC
84 AC AC AC AC
85 CC CC CC CC
86 AC AC AC AC
87 AC AC AC AC
88 AA AA AA AA
89 AC AC AC AC
90 CC CC CC CC
91 CC CC CC CC
92 AC AC AC AC
93 AC AC AC AC
94 AA AA AA AA
95 AC AC AC AC
96 AA AA AA AA
97 AC AC AC AC
98 AC AC AC AC
99 CC CC CC CC
100 AA AA AA AA
101 AC AC AC AC
102 CC CC CC CC
103 CC CC CC CC
104 AA AA AA AA
105 CC CC CC CC
Two of the samples (samples 20 and 30) produced different results by sequencing and SNP analysis. In each case, the sample was genotype AC by sequencing and CC by SNP analysis. Those samples were considered to be inconclusive. Table 2 shows the prevalence of each genotype in the sample set.
Table 2: rs7130929 genotype prevalence
Figure imgf000049_0001
The results of the genotyping for rs4537731 for each sample, as determined by sequencing and by SNP are shown in Table 3. Each sample was sequenced once and subjected to SNP analysis twice. One of the samples failed to sequence. The sample numbers in both Tables 1 and 3 are arbitrary and do not indicate the same sample in both tables. Table 3: rs4537731 genotype
Figure imgf000050_0001
Sample # Sequencing SNP Analysis 1 SNP Analysis 2
53 CT CT CT
54 CT CT CT
55 CC CC CC
56 CT CT CT
57 TT TT TT
58 CC CC CC
59 CC CC CC
60 CC CC CC
61 CT CT CT
62 CT CT CT
63 CT CT CT
64 TT TT TT
65 CT CT CT
66 CT CT CT
67 CT CT CT
68 CC CC CC
69 CT CT CT
70 CC CC CC
71 CT CT CT
72 CT CT CT
73 TT TT TT
74 TT TT TT
75 TT TT TT
76 CT CT CT
77 TT TT TT
78 TT TT TT
79 TT TT TT
80 CT CT CT
81 CT CT CT
82 CT CT CT
83 TT TT TT
84 CT CT CT
85 TT TT TT
86 CT CT CT
87 CT CT CT
88 CC CC CC
89 CT CT CT
90 TT TT CT
91 TT TT TT
92 CT CT CT
93 CT CT CT
94 CC CC CC
95 CT CT CT
96 CC CC CC
97 CT CT CT
98 CT CT CT
99 TT TT TT
100 CC CC CC
101 CT CT CT
102 TT TT TT
103 TT TT TT
104 CC CC CC
105 TT TT TT Table 4 shows the prevalence of each genotype in the sample set.
Table 4: rs4537731 genotype prevalence
Figure imgf000052_0001
The genotype prevalence in the responder subset and non-responder subset of a portion of the study population is shown in Table 5.
Table 5: rs7130929 and rs4537731 genotype in responders and non-responders
Figure imgf000052_0002
Surprisingly, the lower expressing genotypes of the TPHI allele, AA at rs7130929 and CC at rs4537731, were found to correlate with response to the TPHI inhibitor (S)-2-amino-3-(4- (2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid. In contrast, the higher expressing genotypes, CC at rs7130929 and TT at rs4537731, were found to be underrepresented in the responder population. From these results, it appears that the genotypes associated with lower expression of TPHI are predictive of response to TPH inhibitors, such as (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
All of the references (e.g., patents and patent applications) cited herein are incorporated herein by reference in their entireties for any purpose.

Claims

CLAIMS What is claimed is:
1. A method of treating or managing irritable bowel syndrome (IBS), which comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype at a TPH single nucleotide polymorphism (SNP) that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731.
2. The method of claim 1, wherein the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
3. A method of treating or managing irritable bowel syndrome (IBS), which comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs7130929.
4. The method of claim 3, wherein the patient is genotype AA at SNP rs7130929.
5. A method of treating or managing irritable bowel syndrome (IBS), which comprises administering to a patient suffering from IBS a therapeutically or prophylactically effective amount of a TPH inhibitor, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs4537731.
6. The method of claim 5, wherein the patient is genotype CC at SNP rs4537731.
7. The method of any one of claims 1 to 4, wherein the patient suffering from IBS has a genotype selected from CC or CT at SNP rs4537731.
8. The method of claim 7, wherein the patient is genotype CC at SNP rs4537731.
9. A method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy, which comprises determining:
a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of:
i) improvement with defecation,
ii) onset associated with a change in frequency of stool, or
iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731.
10. The method of claim 9, comprising determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
11. A method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy, which comprises determining: a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of:
i) improvement with defecation,
ii) onset associated with a change in frequency of stool, or
iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from AA and AC at SNP rs7130929.
12. The method of claim 11, comprising determining if the patient is genotype AA at SNP rs7130929.
13. A method of determining if a patient suffering from IBS will respond to TPH inhibitor therapy, which comprises determining:
a) if the patient experiences abdominal pain or discomfort at least 3 days/month, which is associated with two or more of:
i) improvement with defecation,
ii) onset associated with a change in frequency of stool, or
iii) onset associated with a change in form (appearance) of stool; and b) if the patient has a genotype selected from CC or CT at SNP rs4537731.
14. The method of claim 13, comprising determining if the patient is genotype CC at SNP rs4537731.
15. The method of any one of claims 9 to 12, wherein the method comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731.
16. The method of claim 15, wherein the method comprises determining if the patient is genotype CC at SNP rs4537731.
17. A method of determining if a patient suffering from non-constipating IBS will respond to TPH inhibitor therapy, which comprises determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929, AC at SNP rs7130929, CC at SNP rs4537731, and CT at SNP rs4537731.
18. The method of claim 17, comprising determining if the patient has a genotype at a TPH SNP that is closely linked to a genotype selected from AA at SNP rs7130929 and CC at SNP rs4537731.
19. A method of determining if a patient suffering from non-constipating IBS will respond to TPH inhibitor therapy, which comprises determining if the patient has a genotype selected from AA and AC at SNP rs7130929.
20. The method of claim 19, comprising determining if the patient is genotype AA at SNP rs7130929.
21. A method of determining if a patient suffering from non-constipating IBS will respond to TPH inhibitor therapy, which comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731.
22. The method of claim 21, comprising determining if the patient is genotype CC at SNP rs4537731.
23. The method of any one of claims 17 to 20, wherein the method comprises determining if the patient has a genotype selected from CC or CT at SNP rs4537731.
24. The method of claim 23, wherein the method comprises determining if the patient is genotype CC at SNP rs4537731.
25. The method of any one of the preceding claims, wherein the IBS is diarrhea- predominant IBS (IBS-D).
26. The method of any one of the preceding claims, wherein the TPH inhibitor is a compound of the formula:
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -0-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)-, -C(R )=C(R )-, -C≡C-, -N(R5)- , -N(R5)C(0)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(Rs)-, -C(R3)NO-, -C(R3R4)0-, -OC(R3R4)- , -S(02)-, -S(02)N(R5)-, -N(R5)S(02)-, -C(R3R4)S(02)-, or -S(02)C(R3R4)-;
D is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl aryl;
each Rs is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
27. The method of claim 26, wherein the compound is of the formula:
Figure imgf000055_0002
28. The method of claim 26, wherein the compound is of the formula:
Figure imgf000056_0001
wherein: each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyi, aryl, or heterocycle; and E is optionally substituted aryl or heterocycle.
29. The method of claim 28, wherein the compound is of the formula:
Figure imgf000056_0002
each Ri is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyi, alkyl-aryl or alkyl-heterocycle;
R2 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyi, alkyl-aryl or alkyl-heterocycle;
R3 is hydrogen, C(0)RA, C(0)ORA, or optionally substituted alkyi, alkyl-aryl, alkyl- heterocycle, aryl, or heterocycle;
R4 is hydrogen or optionally substituted alkyi, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
each RA is independently hydrogen or optionally substituted alkyi, alkyl-aryl or alkyl- heterocycle;
each RB is independently hydrogen or optionally substituted alkyi, alkyl-aryl or alkyl- heterocycle;
each Rc is independently hydrogen or optionally substituted alkyi, alkyl-aryl or alkyl- heterocycle; and
m is 1-4.
30. The method of claim 29, wherein the compound is of the formula:
Figure imgf000056_0003
31. The method of claim 30, wherein the compound is of the formula:
Figure imgf000057_0001
wherein:
each Rs is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and
n is 1-3.
32. The method of claim 31, wherein the compound is of the formula:
Figure imgf000057_0002
wherein:
each R5 is independently halogen, hydrogen, C(0)RA, ORA, NRBRC, S(02)RA, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and
n is 1-3.
33. The method of claim 32, wherein Ri is hydrogen or halogen.
34. The method of claim 32 or claim 33, wherein m is 1.
35. The method of any one of claims 32 to 34, wherein R2 is hydrogen or amino.
36. The method of any one of claims 32 to 35, wherein R4 is hydrogen or Cw alkyl.
37. The method of any one of claims 32 to 36, wherein R5 is hydrogen or lower alkyl.
38. The method of claim 37, wherein Rs is methyl.
39. The method of any one of claims 1 to 26, wherein the compound is (S)-2-amino-3-(4- (2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
40. The method of any one of claims 1 to 26, wherein the compound is (S)-ethyl 2- amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate, or a pharmaceutically acceptable salt thereof.
41. The method of any one of claims 1 to 26, wherein the compound is (S)-2-amino-3-(4- (2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
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