WO2017078928A1 - Agonistes de fxr et procédés de production et d'utilisation - Google Patents

Agonistes de fxr et procédés de production et d'utilisation Download PDF

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WO2017078928A1
WO2017078928A1 PCT/US2016/057532 US2016057532W WO2017078928A1 WO 2017078928 A1 WO2017078928 A1 WO 2017078928A1 US 2016057532 W US2016057532 W US 2016057532W WO 2017078928 A1 WO2017078928 A1 WO 2017078928A1
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compound
alkyl
aliphatic
formula
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Michael Downes
Ronald M. Evans
Thomas J. Baiga
John F.W. Keana
Christopher Liddle
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Salk Institute For Biological Studies
University Of Sydney
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This disclosure concerns new FXR agonists and a method for using the agonists, such as to treat or prevent gastrointestinal (GI) inflammatory conditions, intestinal permeability conditions, intestinal altered microbiome conditions, cholestatic disorders, bile disorders, intestinal absorption disorders, and metabolic disorders, including obesity and diabetes.
  • GI gastrointestinal
  • Metabolic syndrome a western diet-induced, pro-inflammatory disease affecting up to 25% of Americans, is characterized by central obesity, impaired glucose tolerance, dyslipidemia, insulin resistance, and type II diabetes. Secondary complications associated with metabolic syndrome include atherosclerosis, stroke, fatty liver disease, blindness, gallbladder disease, cancer, polycystic ovary disease and others. Consequently there is interest in reducing food intake, losing weight, and reducing elevated blood glucose. There is also an interest in combating obesity and related conditions using methods that do not require drastic lifestyle or dietary changes. In addition, inflammatory gastrointestinal conditions resulting from various types of pathology affect millions of people. Thus, effective and targeted treatments for various inflammatory gastrointestinal (GI) conditions are also needed.
  • GI inflammatory gastrointestinal
  • Farnesoid X receptor is a ligand-activated transcriptional receptor expressed in diverse tissues including the adrenal gland, kidney, stomach, duodenum, jejunum, ileum, colon, gall bladder, liver, macrophages, and white and brown adipose tissue (Forman et al. , Cell 81:687- 693 (1995). FXR has been reported to contribute to the regulation of whole body metabolism including bile acid/cholesterol, glucose and lipid metabolism. Synthetic ligands for FXR have been identified and applied to animal models of metabolic disorders, but these known synthetic ligands have shown limited efficacy and, in certain cases, exacerbated phenotypes.
  • Bile acids function as endogenous ligands for FXR such that enteric and systemic release of BAs induces FXR-directed changes in gene expression networks (Lee et al, Trends Biochem Sci 31:572-580, 2006; Repa et al, Science 289: 1524-1529, 2000; Zollner et al, J Hepatol 39:480-488, 2003; Fang et al,.
  • FXR KO mice develop metabolic defects including hyperglycemia and hypercholesterolemia, but conversely, exhibit improved glucose homeostasis compared to control mice when challenged with a high fat diet (Sinai et al, Cell 102:731-744, 2000; Prawitt et al , Diabetes 60:1861-1871, 2011).
  • FXR activation suppresses hepatic BA synthesis, alters BA composition, reduces the BA pool size (Wang et al , Dev Cell 2:721-731, 2002; Fang et al , Mol Cell Biol 27:1407-1424, 2007; Lu et al, Mol Cell 6:507-515, 2000), and contributes to liver regeneration (Huang et al , Science 312:233-236, 2006) as well as lipid and cholesterol homeostasis (Zhang et al, Genes Dev 18: 157-169, 2004; Ma et al, J Clin Invest 116:1102-1109, 2006).
  • hepatic FXR by the synthetic bile acid 6a-ethyl chenodeoxycholic acid (6- eCDCA) is beneficial in the treatment of diabetes, non-alcoholic fatty liver disease (NAFLD), and primary biliary cirrhosis (PBC) (Stanimirov et al, Acta Gastroenterol Belg 75:389-398, 2012; Mudaliar et al, Gastroenterology 145:574-582 e571, 2013).
  • NASH non-alcoholic fatty liver disease
  • PBC primary biliary cirrhosis
  • FXR is also widely expressed in the intestine where it regulates production of the endocrine hormone FGF15 (FGF19 in humans), which, in conjunction with hepatic FXR, is thought to control BA synthesis, transport and metabolism (Kim et al, J Lipid Res 48:2664-2672, 2007; Song et al,Hepatology 49,:97-305, 2009; Inagak et al, Cell Metab 2:217-225, 2005). Intestinal FXR activity is also known to be involved in reducing overgrowth of the microbiome during feeding (Li et al, Nat Commun 4:2384, 2013; Inagaki et al, Proc Natl Acad Sci U SA 103:3920-3925, 2006).
  • R ⁇ -R 15 independently are selected from hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic, D-heteroaliphatic, or -(CH2) n i-R 150 -(CH2) n 2-R 151 , wherein nl and n2 are independently selected from the group consisting of 0, 1, 2, 3, and 4, R 150 is O, NR 16 , or absent, and R 151 is carboxyl ester or amino; R 16 is selected from hydrogen, aliphatic, D-aliphatic,
  • R a and R b are independently hydrogen, deuterium, aliphatic or D-aliphatic, or together form a bond, such as a pi-bond; and if R a and R b together form a pi-bond then at least one of R ⁇ R 16 is or comprises deuterium.
  • the compound has a formula
  • the com ound has a formula
  • R ⁇ R 16 is or comprises deuterium.
  • R 7 is alkyl or deuterated alkyl, such as isopropyl or a deuterated isopropyl group comprising from 1 to 7 deuterium atoms.
  • at least one of R ⁇ R 5 is a halogen, such as fluoro.
  • R 16 is hydrogen.
  • R 10 and R 11 independently are alkyl or deuterated alkyl, such as methyl or deuterated methyl, wherein the deuterated alkyl group comprises from 1 to n halogen atoms where n is the total number of hydrogen atoms on the substituent, such as from 1 to 3 deuterium atoms for a methyl group.
  • Exemplary compounds having this formula include
  • R 21 -R 34 independently are selected from hydrogen, deuterium, halogen, CX3, where X is a halogen, such as fluorine, with CF3 being a particular example, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D- heteroaliphatic; R 35 is aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic; R 36 is hydrogen, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic; X is N or CR 37 ; and R 37 is hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminos
  • the compound has a formula
  • the compound has a formula
  • R 35 is alkyl, cycloalkyl, deuterated alkyl or deuterated cycloalkyl, such as cyclohexyl or deuterated cyclohexyl comprising 1 to 11 deuterium atoms.
  • R 36 is hydrogen; R 34 is CF3; and R 23 is halogen, such as fluorine or chlorine.
  • Certain compounds are chiral, and all stereoisomers are included in this disclosure.
  • the compound is the most biologically active stereoisomer, such as the S-
  • R 41 -R 48 and R 52 -R 55 independently are selected from hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic,
  • R 49 -R 51 independently are selected from hydrogen, deuterium, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
  • R 56 is amino, cycloamino or substituted cycloamino;
  • Y and Z are independently N or CR 57 ; and each R 57 independently is selected from deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic.
  • Certain compounds are chiral, and all stereoisomers are included in this disclosure.
  • R 41 -R 56 is or comprises deuterium.
  • R 51 is aliphatic or D-aliphatic, such as methyl or deuterated methyl having from 1 to 3 deuterium atoms.
  • R 49 and R 50 independently are hydrogen or deuterium; and
  • R 41 and R 45 independently are aliphatic or D-aliphatic, such as methyl or deuterated methyl having from 1 to 3 deuterium atoms.
  • R 56 is a cycloamino or substituted cycloamino, such as pyrrolidine, 2-methylpyrrolidine, morpholine, 4-
  • R ⁇ -R 57 is -R x -L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S; R x3 is selected from H, aliphatic, or aryl; L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ; R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, -C(0)OR x6 , or -C(0)NR x6 R x7 ; R x6 and R x7 are each independently selected from H, aliphatic; R x2 is selected from -C(0)L x2 R x8 or a carboxyl bioisostere; L x2 is a bond or NR x3 ; R x8 is H, aliphatic, -
  • compositions comprising any such compound, or compounds, and at least one additional component, such as a pharmaceutically exceptable excipient, an additional therapeutic, or combinations thereof, also are disclosed.
  • the compositions may include an enteric coating.
  • Such methods can include administering to the subject a therapeutically effective amount of one or more of the disclosed compounds and/or compositions (such as 1, 2, 3, 4, or 5 of such compounds and/or compositions).
  • Certain method embodiments also may improve glucose and/or lipid homeostasis in the subject.
  • the method further includes administering to the subject a statin, an insulin sensitizing drug, (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or dutoglpitin), meglitinide, sulfonylurea, peroxisome proliferator-activated receptor (alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor PPAR)-gamma agonist (e.g., a thiazolidinedione (TZD) [such as ioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar, farglitazar, muraglitazar, or tesaglitazar), a statin, an insulin
  • ribonucleoside analogs of nicotinamide ribonucleoside, or a combination thereof.
  • the compounds are gut-selective, non-bile acid FXR agonists.
  • absorption of the compounds is substantially limited to the intestines.
  • the compound substantially enhances FXR target gene expression in the intestines while not substantially enhancing FXR target gene expression in the liver or kidney.
  • administering the compounds reduces or prevents diet-induced weight gain and/or increases a metabolic rate in the subject.
  • Increasing the metabolic rate may include enhancing oxidative phosphorylation in the subject.
  • administering the compounds results in no substantial change in food intake and/or fat consumption in the subject, and/or no substantial change in appetite in the subject.
  • Administering the compounds can protect against diet-induced weight gain, reduce inflammation, enhance thermogenesis, enhance insulin sensitivity in the liver, reduce hepatic steatosis, promote browning of white adipose tissue (WAT), promote activation of brown adipose tissue (BAT), decrease blood glucose, increase weight loss, or any combination thereof.
  • administering the compounds enhances insulin sensitivity in the liver and promotes BAT activation.
  • Exemplary metabolic disorders include but are not limited to: obesity, diabetes (such as a
  • BMI of greater than 25, at least 30, at least 35, or at least 40, such as 25 to 30, 35 to 40, or over 40), insulin resistance, dyslipidemia (such as an elevated serum lipids and/or triglycerides, such as a serum LDL of at least 100 mg/dL, such as at least 130 mg/dL, at least 160 mg/dL or at least 200 mg/dL, such as 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 199 mg/dL or greater than 200 mg/dL, and/or such as a serum triglyceride of at least of at least 151 mg/dL, such as at least 200 mg/dL, or at least 500 mg/dL, such as 151 to 199 mg/dL, 200 to 499 mg/dL or greater than 499 mg/dL) or any combination thereof.
  • dyslipidemia such as an elevated serum lipids and/or triglycerides, such as a serum LDL of at least 100 mg/dL
  • the metabolic disorder is non-insulin dependent diabetes mellitus.
  • a method for treating or preventing inflammation such as inflammation in an intestinal region of a subject, are also disclosed.
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, such as 1, 2, 3, 4, or 5 of such compounds and/or compositions activates FXR receptors in the intestines, thereby treating or substantially preventing inflammation in the intestinal region of the subject.
  • the method further includes administering a therapeutically effective amount of an antibiotic (such as metronidazole, vancomycin, and/or fidaxomicin) to the subject, such as to treat or substantially prevent inflammation associated with pseudomembranous colitis in the subject.
  • the method comprises administering to the subject a therapeutically effective amount of an oral corticosteroid and/or other anti-inflammatory or immunomodulatory therapy in combination with the compound, and/or in combination with an antibiotic.
  • Intestinal inflammation may be associated with a clinical condition selected from necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, post-surgical inflammation, gastric carcinogenesis, infectious colitis, or any combination thereof.
  • the one or more FXR target genes comprises IBABP, OSToc, Perl, FGF15, FGF19, or combinations thereof.
  • Embodiments of a method for treating or preventing cholestatic disorders in subject are also disclosed.
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1, 2, 3, 4, or 5 of such compounds, can be used to treat or prevent a cholestatic disorder in subject.
  • Cholestasis is a condition where bile cannot flow (or flow is significantly reduced) from the liver to the duodenum, for example due to a mechanical blockage (e.g. , gallstone, malignancy, or congenital defect), or as a result of a defect in bile formation (e.g., due to a genetic defect, side effect of medication).
  • disorders include, but are not limited to, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), overlap syndrome (PBC plus autoimmune hepatitis), cholestasis resulting from a drug (e.g., one or more of androgen, birth control pills, gold salts, nitrofurantoin, anabolic steroids, chlorpromazine, prochlorperazine, sulindac, cimetidine, estrogen, statins, and antibiotics such as TMP/SMX, flucoxacillin and erythromycin), drug-induced cholestatic hepatitis, total parenteral nutrition (TPN) -induced cholestasis, ICU/sepsis-related cholestasis, obstetric cholestasis, graft vs.
  • a drug e.g., one or more of androgen, birth control pills, gold salts, nitrofurantoin, anabo
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as
  • ursodeoxycholic acid phenobarbital, methotrexate, fat-soluble vitamins, or combinations thereof
  • ursodeoxycholic acid phenobarbital, methotrexate, fat-soluble vitamins, or combinations thereof
  • Embodiments of a method for treating or preventing intestinal permeability conditions in subject are also disclosed.
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1, 2, 3, 4, or 5 of such compounds can be used to treat or prevent an intestinal permeability condition in subject.
  • Intestinal permeability is a condition where the gut wall exhibits excessive permeability (which some in the field call leaky gut syndrome). Examples of such disorders include, but are not limited to, Crohn's disease, ulcerative colitis, infectious colitis, celiac disease, type 1 diabetes, inflammatory bowel disease, irritable bowel syndrome, or any combination thereof.
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as glutamine, prebiotics, probiotics, Escherichia coli Nissle 1917, or combinations thereof) to the subject, such as to treat or substantially prevent one or more intestinal permeability disorders in the subject.
  • another therapeutic agent such as glutamine, prebiotics, probiotics, Escherichia coli Nissle 1917, or combinations thereof
  • Embodiments of a method for treating or preventing disorder that causes or results from an altered intestinal microbiome in subject are also disclosed.
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1, 2, 3, 4, or 5 of such compounds can be used to treat or prevent a disorder resulting altered intestinal microbiome in subject.
  • An altered intestinal microbiome is a condition where the abundance and/or types of bacteria (such as Bacteriodes. E. coli, Lactobacillus, and Bifidobacteria species) and other microbes (such as yeast) in the intestine are abnormal.
  • disorders that can have an altered gut microbiome include, but are not limited to, celiac disease, the intestinal permeability conditions described herein, the intestinal inflammation disorders described herein, alcoholic hepatitis, necrotizing enterocolitis, Crohn's disease, ulcerative colitis, intestinal lesions (such as those in a cystic fibrosis patient), cirrhosis, or any combination thereof.
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as a fecal microbiota transplant,
  • immunosuppressant antibiotic, mesalamine, steroid, altered diet, or combinations thereof
  • the subject such as to treat or substantially prevent one or more disorders resulting from or that causes an altered intestinal microbiome in the subject.
  • a method for treating an inborn error of metabolism in subject are also disclosed. Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1 , 2, 3, 4, or 5 of such compounds, can be used to treat or prevent an inborn error of metabolism in subject.
  • an inborn error of metabolism is a genetic condition resulting in accumulation of substance which interfere with normal function or the reduced ability to synthesize essential compounds, (such as a reduction in bile acid production, lipid production, or lipid storage).
  • One example of an inborn error of metabolism is cerebrotendinous xanthomatosis (CTX).
  • CX cerebrotendinous xanthomatosis
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as chenodeoxycholic acid (CDCA), an HMG-CoA reductase inhibitor ("statins" such as simvastatin) or combinations thereof) to the subject, such as to treat an inborn error of metabolism in the subject.
  • another therapeutic agent such as chenodeoxycholic acid (CDCA), an HMG-CoA reductase inhibitor (“statins” such as simvastatin) or combinations thereof
  • Embodiments of a method for treating or preventing a bile disorder in subject are also disclosed.
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1 , 2, 3, 4, or 5 of such compounds can be used to treat or prevent a bile disorder in subject.
  • Bile disorders include mechanical biliary obstructions, disorders that result from bile acid malabsorption, and bile acid synthesis disorders. Examples of bile disorders that can be treated with the disclosed compounds include, but are not limited to, benign biliary stricture, malignant biliary obstruction, bile acid diarrhea, or any combination thereof.
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as bile acid sequestrant, cholestyramine, colestipol, farnesoid X receptor agonist (such as obeticholic acid), or combinations thereof) to the subject, such as to treat or prevent a bile disorder in the subject.
  • another therapeutic agent such as bile acid sequestrant, cholestyramine, colestipol, farnesoid X receptor agonist (such as obeticholic acid), or combinations thereof
  • Embodiments of a method for treating or preventing a malabsorption disorder e.g., intestinal malabsorption
  • a malabsorption disorder e.g., intestinal malabsorption
  • short bowel syndrome or symptoms arising from such, such as diarrhea, steatorhea, malnutrition, fatigue, vitamin deficiency), environmental enteropathy, or tropical sprue
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1, 2, 3, 4, or 5 of such compounds can be used to treat a malabsorption disorder in subject.
  • Short bowel syndrome is a malabsorption disorder causes by surgical removal of the small intestine or dysfunction of a large segment of bowel. Short bowel syndrome can be caused by a birth defect, Crohn' s disease, volvulus, tumors, injury, necrotizing enterocolitis, or surgery.
  • the method further includes administering a therapeutically effective amount of another therapeutic agent (such as an anti- diarrheal medicine such as loperamide or codeine, vitamin supplement (such as B12 and folic acid), mineral supplement, L glutamine, proton pump inhibitors, lactase, tedulutide (a glucagon-like peptide-2 analog), total parenteral nutrition, antibiotic (e.g., tetracycline or
  • sulfamethoxazole/trimethoprim or combinations thereof to the subject, such as to treat or prevent a malabsorption disorder in the subject.
  • Embodiments of a method for treating or preventing a cell proliferation disease e.g., cancer, such as adenocarcinoma, such as cancer of the colon, jejunum, and/or ileum
  • a cell proliferation disease e.g., cancer, such as adenocarcinoma, such as cancer of the colon, jejunum, and/or ileum
  • Administering to a subject a therapeutically effective amount of one or more of the disclosed compounds, or one or more of the disclosed compositions, such as 1, 2, 3, 4, or 5 of such compounds and/or compositions activates FXR receptors in the intestines, thereby treating or substantially preventing a cell proliferation disease, for example in the intestinal region of the subject.
  • the method further includes administering a therapeutically effective amount of another therapeutic agent, (such as a chemotherapeutic, a biologic, a radio therapeutic, or combinations thereof) to the subject, such as to treat or substantially prevent a cell proliferation disease in the subject.
  • a therapeutically effective amount of another therapeutic agent such as a chemotherapeutic, a biologic, a radio therapeutic, or combinations thereof
  • the method may increase HSL phosphorylation and ⁇ 3- adrenergic receptor expression (such as an increase of at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, or at least 100%). Additionally, the serum concentration of the compound in the subject may remain below its EC50 following administration of the compound.
  • FIGS. 1A-1C are a comparative expression chart and two bar charts, respectively, illustrating increased levels of FXR target gene expression in the intestine relative to expression in the liver and kidney.
  • 8 week-old C57BL/6J mice were treated with vehicle or fexaramine (100 mg/kg) via oral (PO) or intraperitoneal (IP) injection for three days (FIGS. 1A- 1B) or five days (FIG. 1C).
  • FIG. 1A shows FXR target SHP gene expression in FXR abundant tissues including liver, kidney and intestine from 8 week-old mice that were treated with vehicle or fexaramine (100 mg/kg) via oral (PO) or intraperitoneal (IP) injection for three days.
  • FXR target gene expression was analyzed by qPCR. Gene expression was normalized against a vehicle-treated group.
  • FIG. IB shows that PO administration of fexaramine (solid bars), but not vehicle (open bars), substantially enhances FXR target gene expression in the intestine, and not in the liver or kidney.
  • FIG. 1C shows that IP injection of fexaramine increases FXR target gene expression in the liver and kidney, in addition to the intestines. Data represent the mean + SD. Statistical analysis was performed with the Student's t test. *p ⁇ 0.05, **p ⁇ 0.01
  • FIG. ID is a schematic diagram illustrating an experimental procedure used to evaluate fexaramine, where mice were treated with vehicle or fexaramine (100 mg/kg) via PO or IP injection, and LC/MS quantification of serum fexaramine was conducted five days later.
  • FIG. IE is a bar chart illustrating serum fexaramine concentrations after administration as described in FIG. ID. Data represent mean values + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. IF is a bar chart illustrating that orally delivered fexaramine is intestinally-restricted.
  • mice received vehicle or Fexaramine (lOOmg/kg) via per os (PO) or intraperitoneal (IP) injection for 5 days. Expression of the FXR target gene SHP after PO or IP injection in selected tissues is shown.
  • FIGS. 2A-2G are graphs illustrating the reduction of diet-induced obesity and improvement in metabolic homeostasis with fexaramine.
  • Mice were fed a high fat diet (HFD) for 14 weeks and then administered daily oral injections of vehicle (open boxes) or fexaramine (100 mg/kg) (solid boxes) for 5 weeks with HFD. Data represent the mean + STD.
  • Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 2B shows mice body weight composition by MRI at the completion of the study.
  • FIG. 2C shows the wet weight of inguinal fat (iWAT), gonadal fat (gWAT), mesenteric fat (mWAT), liver, kidney, heart and spleen at the completion of the study.
  • iWAT inguinal fat
  • gWAT gonadal fat
  • mWAT mesenteric fat
  • FIG. 2D shows the serum levels (samples were collected after 8 hours-fasting for parameter analysis) of insulin, cholesterol, leptin, resistin and triglycerides.
  • FIG. 2E shows the serum levels of cytokines at the completion of the study.
  • FIG. 2F is a line graph representing glucose tolerance testing (GTT), which revealed that fexaramine treatment improved glucose clearance.
  • FIG. 2G is a line graph representing insulin tolerance testing (ITT), which showed that fexaramine treatment improved insulin sensitivity.
  • FIGS. 3A-3D are line graphs and a bar graph showing the effects of fexaramine administration in normal chow-fed mice.
  • the mice were treated with vehicle (left bar) or fexaramine (100 mg/kg) (right bar) via PO for 5 weeks.
  • Data represent the mean + STD.
  • Statistical analysis as performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 3A is a line graph showing hourly composite carbon dioxide production.
  • FIG. 3B is a line graph showing hourly composite oxygen consumption.
  • FIG. 3C is a glucose tolerance test.
  • FIG. 3D is a bar graph showing core body temperature.
  • FIG. 4A is a line graph showing the effects of fexaramine at various dosage levels on the body weight of mice fed a HFD for 14 weeks and then administered daily oral injections of vehicle or fexaramine (10, 50 or 100 mg/kg) for 5 weeks with HFD. Data represent the mean + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 4B is a set of digital images showing histological analysis of the ileum and colon following treatment with fexaramine or vehicle. Mice were fed on HFD for 14 weeks, and then administered daily oral injections of vehicle or fexaramine (100 mg/kg) for 5 weeks with HFD.
  • FIG. 4C is a line graph showing glucose tolerance tests in mice fed a HFD for 14 weeks and then administered daily oral injections of vehicle or fexaramine (10, 50 or 100 mg/kg) for 5 weeks with HFD. Data represent the mean + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 4D is a line graph showing fasting glucose levels in 14 week HFD-fed mice treated with vehicle or fexaramine (lOOmg/kg/day os for 5 week). Data represent the mean + STD.
  • FIGS. 5A-5I show that FXR is required for fexaramine's effects
  • A Body weights
  • B glucose tolerance test
  • C insulin tolerance test
  • D oxygen consumption
  • E carbon dioxide production
  • F core body temperature
  • G brown adipose tissue gene expression
  • H liver gene expression
  • I FXR target gene expressions in ileum of 14 week HFD fed FXR-null mice treated with vehicle or fexaramine (lOOmg/kg) for 5 week with HFD.
  • Data represent the mean + SD.
  • Statistical analysis was performed with the Student's t test. *p ⁇ 0.05, **p ⁇ 0.01.
  • FIGS. 6A-6J demonstrate that fexaramine increases OXPHOS to enhance metabolic rate in brown adipose tissue.
  • Mice were fed HFD for 14 weeks and then administered vehicle or fexaramine (100 mg/kg) daily by oral administration for 5 weeks with HFD. Data represent the mean + STD.
  • Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 6A is a bar chart showing daily food intake during the first week treatment.
  • FIG. 6B is a line chart showing carbon dioxide production.
  • FIG. 6C is a line chart showing oxygen consumption.
  • FIG. 6D is a bar chart showing daytime and nighttime cumulative ambulatory counts.
  • FIG. 6E is a bar chart showing core body temperature.
  • FIG. 6F shows hematoxlyin and eosin staining of brown adipose tissue (BAT) for histological analysis.
  • FIG. 6G is a bar chart showing relative gene expression of nuclear receptors and other genes encoding proteins involved in mitochondrial biogenesis, glucose transport and FA oxidation in BAT.
  • FIG. 6H is a set of digital images of gel electrophoreses showing protein expression levels of total and phosphorylated p38 in BAT. RalA levels are shown as a loading control.
  • FIG. 61 is a bar chart showing the relative levels of phosphorylated p38 in BAT after vehicle (open bar) or Fexaramine administration (solid bar).
  • FIG. 6J is a chart showing changes in relative expression of OXPHOS genes based on
  • iWAT inguinal fat
  • gWAT gonadal fat
  • BAT brown fat
  • FIG. 6K is a heatmap depiction of changes in genes involved in chemokine and cytokine signaling in BAT after vehicle or fexaramine treatment.
  • FIG. 6L is a bar graph showing PKA activity in BAT. Data represent the mean + SD.
  • FIG. 6M is a bar chart showing the effect of fexaramine on respiratory exchange ratio (RER). Mice were fed on HFD for 14 weeks, and then administered daily oral injections of vehicle (solid bar) or fexaramine (100 mg/kg) (open bar) for 5 weeks with HFD. No changes were observed in respiratory exchange ratio by fexaramine treatment.
  • FIG. 6N is a bar graph showing the effect of fexaramine administration on serum lactate concentrations. Mice were fed on HFD for 14 weeks, and then administered daily oral injections of vehicle (left bar) or fexaramine (100 mg/kg) (right bar) for 5 weeks with HFD. Serum lactate levels were found to be significantly decreased with fexaramine treatment. Data represent the mean + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIGS. 7A-7H show a comparative expression chart and bar charts illustrating that fexaramine increased endogenous FGF15 signaling and changes in BA composition.
  • Mice were fed HFD for 14 weeks and then administered daily oral injections of vehicle or fexaramine (100 mg/kg) for 5 weeks with HFD.
  • open bars represent vehicle treatment and solid bars represent fexaramine treatment, and data represent the mean + STD.
  • Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 7A is a heatmap depicting changes in expression of ileal FXR target genes following PO fexaramine administration.
  • FIG. 7B is a bar chart showing FGF15 protein levels from ileal extract.
  • FIG. 7C is a bar chart showing FGF15 protein levels in the serum.
  • FIG. 7D is a bar chart showing changes in the expression of hepatic genes involved in bile acid metabolism.
  • FIG. 7E is a bar chart showing total serum bile acid (BA) levels.
  • FIG. 7F is a bar chart showing composition ratios of bile acids. The ratio of unconjugated to conjugated cholic acid was remarkably increased by fexaramine.
  • FIG. 7G is a bar chart showing changes in intestinal permeability.
  • FIG. 7H is a bar chart showing changes in expression of intestinal genes involved in mucosal defense.
  • FIG. 8 is a bar graph showing hepatic Cyp7al levels determined by ELISA. Data represent the mean + SD. Statistical analysis was performed with the Student's t test. *p ⁇ 0.05, **p ⁇ 0.01.
  • FIG. 9 is a bar graph showing that fexaramine fails to activate TGR5.
  • HEK293 cells were transfected with expression vectors for cAMP-response element luciferase, ⁇ -galactosidase and human TGR5. 24 hours after transfection, cells were treated with fexaramine or INT-777 (a TGR5 agonist).
  • FIGS. 10A-10F show that systemic TGR5 activation is required to affect glucose homeostasis.
  • HFD-fed mice were treated with vehicle, the intestinally-restricted TGR5 ligand L755-0379 (A, L755, lOOmg/kg, EC50 300nM) or the systemic ligand R05527239 (B, RO, lOOmg/kg. EC50 70nM) via per os for 14 days.
  • C Plasma L755 concentrations in portal and tail veins after PO administration.
  • D Body weight curve.
  • E Glucose tolerance test.
  • F Serum insulin levels after a glucose challenge (vehicle left bar, RO middle bar, L755 right bar). Data represent the mean + SD.
  • A Ileal FXR target gene expressions
  • B Serum BA levels
  • C Fasting glucose levels
  • D Glucose tolerance test
  • E Core body temperature
  • F Oxygen consumption rate
  • G Carbon dioxide production
  • H Gene expression in BAT
  • I Body weight curve
  • J Body composition by MRI
  • K Insulin Tolerance Test
  • L Hepatic gene expression
  • N Hepatic TG levels
  • FIGS. 12A-12H demonstrate that fexaramine reduces inflammation and increases lipolysis in adipose tissues.
  • Mice were fed on HFD for 14 weeks and subsequently subjected to daily PO injection of vehicle or fexaramine (100 mg/kg) for 5 weeks with HFD.
  • open bars are vehicle
  • solid bars of fexaramine represent the mean + STD.
  • Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 12A shows histological sections of mesenteric white adipose tissues from vehicle and fexaramine-treated mice.
  • FIG. 12B is a set of photographs of gel electrophoreses showing protein expression levels of TBK1, and total and phosphorylated ⁇ and S6K, in gonadal adipose tissues (gWAT) from vehicle or fexaramine-treated mice.
  • FIG. 12C is a bar chart showing relative gene expression levels of ⁇ -3-adrenergic receptor and various cytokines in gonadal adipose tissue. Vehicle open bar, Fex solid bar.
  • FIG. 12D is a set of photographs of gel electrophoreses showing protein expression levels of total and phosphorylated HSL (p-HSL) and p65 in gonadal and inguinal adipose tissues.
  • FIG. 12E is a bar chart showing serum levels of catecholamines, in vehicle or fexaramine- treated mice. Vehicle open bar, Fex solid bar.
  • FIG. 12F is a bar chart showing serum glycerol levels, in vehicle or fexaramine-treated mice. Isoproterenol ( ⁇ g/kg) was injected at 0 minutes and free glycerol levels were measured at the indicated time points. Vehicle left bar, Fex right bar.
  • FIG. 12G is a bar chart showing serum levels of free fatty acids in vehicle or fexaramine - treated mice. Data represent the mean + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01). Vehicle open bar, Fex solid bar.
  • FIG. 12H shows UCP1 staining of brown fat-like cells in inguinal adipose tissues (iWAT) from vehicle or fexaramine-treated mice (Magnification: 100X).
  • FIGS. 121 and 12J show that fexaramine enhances OXPHOS in iWAT. Mice fed a HFD for 14 weeks were maintained on a HFD and treated with vehicle or fexaramine (lOOmg/kg/day os for 5 week).
  • FIG. 13 is a set of digital images of gel electrophoreses (Western blots) showing the level of expression of various proteins in gonadal white adipose tissue (gWAT). Mice fed a HFD for 14 weeks were maintained on a HFD and treated with vehicle or fexaramine (50mg or lOOmg/kg/day os for 5 week).
  • FIG. 14 is a bar chart showing that fexaramine reduces brown adipose tissue (BAT) inflammation.
  • Mice fed a HFD for 14 weeks were maintained on a HFD and treated with vehicle or fexaramine (lOOmg/kg/day os for 5 week).
  • Data represent the mean + SD.
  • Statistical analysis was performed with the Student's t test. *p ⁇ 0.05, **p ⁇ 0.01.
  • FIGS. 15A-15H are a set of histology stains and bar charts demonstrating that fexaramine induced less weight gain and improved glucose homeostasis relative to mice that did not receive fexaramine. Mice were fed HFD for 14 weeks and then subjected to daily PO injection of vehicle (open bar in bar graphs) or fexaramine (100 mg/kg) (solid bar in bar graphs) for 5 weeks with HFD.
  • FIG. 15A is a bar chart showing basal hepatic glucose production (HGP).
  • FIG. 15B is a bar chart showing glucose disposal rate (GDR).
  • FIG. 15C is a bar chart showing percentage free fatty acid (FFA) suppression by insulin.
  • FIG. 15D is a bar chart showing HGP suppression by insulin, as measured by
  • FIG. 15E shows hematoxylin and eosin staining for liver histology.
  • FIG. 15F is a bar chart showing triglyceride levels in the liver.
  • FIG. 15G is a bar chart showing hepatic gene expression levels for genes involved in gluconeogenesis and lipogenesis.
  • FIG. 15H is a bar chart showing serum levels of alanine aminotransferase (ALT). Vehicle open bar, Fex, solid bar.
  • FIGS. 15I-15K are a line graph and two bar graphs showing the effect of fexaramine treatment on body weight, insulin-stimulated GDR, and fasting insulin levels.
  • Mice were fed HFD for 14 weeks, and then administered daily oral injections of vehicle or fexaramine (100 mg/kg) for 3 weeks with HFD. The mice treated with fexaramine were initially heavier (by 2-3 grams). Three weeks after treatment, a clamp study was performed on the mice. Data represent the mean + STD. Statistical analysis was performed with the Student's t test (*p ⁇ 0.05, **p ⁇ 0.01).
  • FIG. 151 is a line graph showing the changes in body weight for the two groups of mice. Vehicle bottom line, Fex, top line.
  • FIG. 15J is a bar chart showing the insulin-stimulated GDR (IS-GDR). Vehicle left bar,
  • FIG. 15K is a bar chart showing the fasting insulin levels. Vehicle left bar, Fex, right bar.
  • amino acid sequences are shown using standard three letter code for amino acids, as defined in 37 C.F.R. 1.822.
  • SEQ ID NO. 1 is a protein sequence of GLP-l-(7-36).
  • SEQ ID NO. 2 is a protein sequence of GLP-2. DETAILED DESCRIPTION
  • Aliphatic refers to a substantially hydrocarbon-based compound, or a radical thereof (e.g., C 6 Hi3, for a hexane radical), including alkanes, alkenes, alkynes, including cyclic versions thereof, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well.
  • an aliphatic group contains from one to at least twenty-five carbon atoms; for example, from one to fifteen, from one to ten, from one to six, or from one to four carbon atoms.
  • lower aliphatic refers to an aliphatic group comprising from one to ten carbon atoms.
  • An aliphatic chain may be substituted or unsubstituted. Unless expressly referred to as an "unsubstituted aliphatic," an aliphatic group can either be unsubstituted or substituted.
  • Exemplary aliphatic substituents include, for instance, amino, amide, sulfonamide, halo, cyano, carboxy, hydroxyl, mercapto, trifluoromethyl, alkyl, alkoxy, acetoxy, alkylthio, thioalkoxy, arylalkyl, heteroaryl, alkylamino, dialkylamino, or other functionality.
  • D-aliphatic refers to an aliphatic group where at least one hydrogen has been substituted by deuterium.
  • Amino refers to the group -NR'R", wherein R' and R" independently are selected from hydrogen, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic, or where R' and R" are optionally joined together with the nitrogen bound thereto to form a cycloamino group such as a heterocyclic, deuterated heterocyclic, heteroaryl or deuterated heteroaryl group comprising at least one ring nitrogen.
  • Exemplary cycloamino groups include, but are not limited to, pyrrolidine, pyrrole, imidazole, triazole, tetrazole, piperidine, triazinane, piperazine, morpholine, azepane, diazepane, azocane, diazocane, azonane or azecane.
  • a primary aminocarbonyl is -CONH2.
  • cyano refers to the chemical functional group -CN.
  • carboxyl ester refers to the chemical functional group -CO2R where R is aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic.
  • aminosulfonyl refers to a chemical function group -SC -amino, where amino is as defined herein. A primary aminosulfonyl is -SO2NH2.
  • acyl means, unless otherwise stated, -C(0)R where R is aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic.
  • aryl refers to a monovalent aromatic carbocyclic group of from 6 to 15 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) in which at least one of the condensed rings is aromatic (e.g., 2-benzoxazolinone, 2H-1,4- benzoxazin-3(4H)-one-7-yl, 9, 10-dihydrophenanthrene, and the like), provided that the point of attachment is through an atom of the aromatic aryl group. Unless otherwise specified, the aryl group may be optionally substituted. Preferred aryl groups include phenyl and naphthyl.
  • Heteroaliphatic refers to an aliphatic compound or group having at least one heteroatom, i.e. , one or more carbon atoms has been replaced with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic", or “heterocyclic” groups. Examples of heterocycles include morpholine and piperidine.
  • D-heteroaliphatic refers to a heteroaliphatic group where at least one hydrogen has been substituted by a deuterium.
  • Halo refers to fluoro, chloro, bromo, and iodo, and is preferably fluoro or chloro.
  • Heteroaryl refers to an aromatic group having from 1 to 15 carbon atoms and at least one, and more typically 1 to 4, heteroatoms selected from oxygen, nitrogen or sulfur within the ring. Unless otherwise specified, the heteroaryl group may be optionally substituted.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl or furyl) or multiple condensed rings (e.g., indolizinyl, quinolinyl, benzimidazolyl, benzopyrazolyl or benzothienyl), wherein at least one of the condensed rings is aromatic and may or may not contain a heteroatom, provided that the point of attachment is through an atom of an aromatic ring.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, benzopyrazolyl and furanyl.
  • “Sulfonyl” refers to the group -SO2-, and includes -S02-aliphatic, -SC -aryl,
  • -S02-heteroaryl or -S02-heterocyclic, wherein aliphatic, aryl, heteroaryl, and heterocyclic are as defined herein.
  • Sulfonyl includes groups such as methyl-SC -, phenyl-S0 2 -, and 4- methylphenyl-SC -.
  • carboxyl bioisosteric or “carboxyl bioisostere” refer to a group with similar physical or chemical properties to a carboxyl groupthat produce broadly similar biological properties, but which may reduce toxicity or modify the activity of the compound, and may alter the metabolism of the compound.
  • Exemplary carboxyl bioisosteres include, but are not limited to,
  • X 7 , Y 7 , and Z 7 are each independently
  • a group that is substituted has 1 substituent, 1 or 2 substituents, 1, 2, or 3 substituents or 1, 2, 3 or 4 substituents.
  • impermissible substitution patterns are understood by a person having ordinary skill in the art.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. If the molecule contains a basic functionality, pharmaceutically acceptable salts include salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • “Pharmaceutically acceptable excipient” refers to a substantially physiologically inert substance that is used as an additive in a pharmaceutical composition. As used herein, an excipient may be incorporated within particles of a pharmaceutical composition, or it may be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, as a carrier, flavoring agent, thickener, diluent, buffer, preservative, or surface active agent and/or to modify properties of a pharmaceutical composition.
  • excipients include, but are not limited, to polyvinylpyrrolidone (PVP), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, sodium citrate, and lactose.
  • PVP polyvinylpyrrolidone
  • DPPC dipalmitoyl phosphatidyl choline
  • trehalose sodium bicarbonate
  • glycine sodium citrate
  • lactose lactose
  • Enteric coating refers to a coating such as may be applied to disclosed compounds or compositions comprising the compounds to help protect drugs from disintegration, digestion etc. in the stomach, such as by enzymes or the pH of the stomach. Typically, the coating helps prevent the drug from being digested in the stomach, and allows delivery of the medication to the intestine.
  • administer refers to methods that may be used to enable delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes and rectal administration. Administration techniques that are optionally employed with the agents and methods described herein are found in sources e.g., Goodman and Gilman, The
  • agents and compositions described herein are administered orally.
  • calorie refers to the amount of energy, e.g. heat, required to raise the temperature of 1 gram of water by 1 °C.
  • the term “calorie” is often used to describe a kilocalorie.
  • a kilocalorie is the amount of energy needed to increase the temperature of 1 kilogram of water by 1 °C.
  • One kilocalorie equals 1000 calories.
  • the kilocalorie is abbreviated as kc, kcal or Cal, whereas the calorie or gram calorie is abbreviated as cal.
  • food intake in the subject is measured in terms of overall calorie consumption.
  • fat intake can be measured in terms of calories from fat.
  • the terms "co-administration,” “administered in combination with,” and their grammatical equivalents, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the agents described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the agents described herein and the other agent(s) are administered in a single composition.
  • the agents described herein and the other agent(s) are admixed in the composition.
  • an “effective amount,” “pharmaceutically effective amount” or “therapeutically effective amount” as used herein, refer to a sufficient amount of at least one agent being administered to achieve a desired result, e.g., to relieve to some extent one or more symptoms of a disease or condition being treated. In certain instances, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In certain instances, an “effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.
  • Enhancing enteroendocrine peptide secretion refers to a sufficient increase in the level of the enteroendocrine peptide agent to, for example, decrease hunger in a subject, to curb appetite in a subject and/or decrease the food intake of a subject or individual and/or treat any disease or disorder described herein.
  • FXR farnesoid X receptor (also known as nuclear receptor subfamily 1, group H, member 4 (NR1H4)) (OMIM: 603826): This protein functions as a receptor for bile acids, and when bound to bile acids, regulates the expression of genes involved in bile acid synthesis and transport. FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes.
  • NR1H4 nuclear receptor subfamily 1, group H, member 4
  • FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol.
  • CYP7A1 cholesterol 7 alpha-hydroxylase
  • FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.
  • FXR sequences are publically available, for example from GenBank® sequence database (e.g., accession numbers NP_001193906 (human, protein) and NP_001156976 (mouse, protein), and NM_001206977 (human, nucleic acid) and NM_001163504 (mouse, nucleic acid)).
  • GenBank® sequence database e.g., accession numbers NP_001193906 (human, protein) and NP_001156976 (mouse, protein), and NM_001206977 (human, nucleic acid) and NM_001163504 (mouse, nucleic acid)).
  • metabolic disorder refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids or a combination thereof.
  • a metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or carbohydrates.
  • Factors affecting metabolism include, but are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP- 1, GLP-2, oxyntomodulin, PYY or the like), the neural control system (e.g. , GLP- 1 in the brain) or the like.
  • Examples of metabolic disorders include and are not limited to diabetes, insulin resistance, dyslipidemia, metabolic syndrome, or the like.
  • the term "metabolic rate” refers to the rate at which the subject uses energy. This is also known as the rate of metabolism, or the rate of energy consumption, and reflects the overall activity of the individual's metabolism.
  • basal metabolism refers to the minimum amount of energy required to maintain vital functions in an individual at complete rest, measured by the basal metabolic rate in a fasting individual who is awake and resting in a comfortably warm environment.
  • basal metabolic rate refers to the rate at which energy is used by an individual at rest. Basal metabolic rate is measured in humans by the heat given off per unit time, and expressed as the calories released per kilogram of body weight or per square meter of body surface per hour. The heart beating, breathing, maintaining body temperature, and other basic bodily functions all contribute to basal metabolic rate.
  • Basal metabolic rate can be determined to be the stable rate of energy metabolism measured in individuals under conditions of minimum environmental and physiological stress, or essentially at rest with no temperature change. The basal metabolic rate among individuals can vary widely. One example of an average value for basal metabolic rate is about 1 calorie per hour per kilogram of body weight.
  • the terms "non- systemic” or “minimally absorbed” as used herein refer to low systemic bioavailability and/or absorption of an administered compound. In some instances a non-systemic compound is a compound that is substantially not absorbed systemically.
  • FXR agonist compositions described herein deliver an FXR agonist to the distal ileum, colon, and/or rectum and not systemically (e.g., a substantial portion of the FXR agonist administered is not systemically absorbed).
  • the systemic absorption of a non-systemic compound is ⁇ 0.1%, ⁇ 0.3%, ⁇ 0.5%, ⁇ 0.6%, ⁇ 0.7%, ⁇ 0.8%, ⁇ 0.9%, ⁇ 1%, ⁇ 1.5%, ⁇ 2%, ⁇ 3%, or ⁇ 5% of the administered dose (wt. % or mol %).
  • the systemic absorption of a non-systemic compound is ⁇ 15% of the administered dose.
  • the systemic absorption of a non-systemic compound is ⁇ 25% of the administered dose.
  • a non-systemic FXR agonist is a compound that has lower systemic bioavailability relative to the systemic bioavailability of a systemic FXR agonist.
  • the bioavailability of a non-systemic FXR agonist described herein is ⁇ 30%, ⁇ 40%, ⁇ 50%, ⁇ 60%, or ⁇ 70% of the bioavailability of a systemic FXR agonist.
  • the serum concentration of the FXR agonist in the subject remains below the compound's EC50 following administration.
  • prevent include preventing additional symptoms, preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition and are intended to include prophylaxis.
  • the terms further include achieving a prophylactic benefit.
  • the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient reporting one or more of the physiological symptoms of a disease, or to a patient at risk of reoccurrence of the disease.
  • subject may be used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish, amphibians, and the like.
  • the mammal is a human.
  • treat include alleviating, inhibiting or reducing symptoms, reducing or inhibiting severity of, reducing incidence of, prophylactic treatment of, reducing or inhibiting recurrence of, preventing, delaying onset of, delaying recurrence of, abating or ameliorating a disease or condition symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms further include achieving a therapeutic benefit.
  • Therapeutic benefit means eradication or amelioration of the underlying disorder being treated, and/or the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient.
  • an FXR agonist to the GI tract of a subject, such as one of the novel FXR agonists disclosed herein.
  • methods for treating or preventing a cell proliferative disorder, such as cancer, for example in the intestine by administering a therapeutically effective amount of an FXR agonist to the subject (e.g., to the GI tract), such as one of the novel FXR agonists disclosed herein.
  • the absorption of these FXR agonists may be substantially restricted to the intestinal lumen when delivered orally.
  • administration of one or more of the disclosed FXR agonists may result in activation of FXR transcriptional activity in the intestine, without substantially affecting other target tissues, such as liver or kidney. Despite this restricted activity, chronic administration with these agonists may lead to beneficial body-wide effects in obese subjects.
  • the disclosed FXR agonists may have potent anti-obesity and glucose lowering effects in vivo. These effects have not been observed with systemically-acting FXR ligands and may include reductions in weight gain, hyperglycemia, and/or insulin resistance.
  • administration of these FXR agonists may produce a beneficial, anti-inflammatory effect in the intestines.
  • a compound that may have activity as an FXR agonist include compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI and XVII. Certain compounds are chiral, and all stereoisomers are included in this disclosure, as well as all geometric and structural isomers cis and trans isomers.
  • R ⁇ -R 15 independently are selected from hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic, D-heteroaliphatic, or -(CH2) n i-R 150 -(CH2) n 2-R 151 , wherein nl and n2 are independently selected from the group consisting of 0, 1, 2, 3, and 4, R 150 is O, NR 16 , or absent, and R 151 is carboxyl ester or amino; R 16 is selected from hydrogen, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic; R a and R b are independently hydrogen, deuterium, aliphatic or D-aliphatic, or together form a pi-bond.
  • R ⁇ R 16 is -R x -L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S; R x3 is selected from H, aliphatic, or aryl; L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ; R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, -C(0)OR x6 , or -C(0)NR x6 R x7 ; R x6 and R x7 are each independently selected from H, aliphatic; R x2 is selected from -C(0)L x2 R x8 or a carboxyl bioisostere; L x2 is a bond or NR x3 ; R x8 is H, aliphatic, -OR x9
  • At least one of R ⁇ R 16 is or comprises deuterium.
  • R 7 may be H, aliphatic, heteroaliphatic or D-heteroaliphatic.
  • R 7 is alkyl or deuterated alkyl, and in certain embodiments, R 7 is isopropyl or deuterated isopropyl, having from 1 to 7 deuterium atoms.
  • At least one of R ⁇ R 5 is a halogen.
  • R 2 and R 3 are both fluoro.
  • R 16 is hydrogen
  • R 10 and R 11 independently are alkyl or deuterated alkyl, and in certain examples, R 10 and R 11 independently are methyl or deuterated methyl, having from 1 to 3 deuterium atoms. In some embodiments, R a and R b together form a pi-bond, leading to compounds have formula II
  • R ⁇ R 16 are as defined above with respect to formula I, and at least one of R ⁇ R 15 is or comprises deuterium.
  • R a and R b are both hydrogen, leading to compounds having a formula III
  • Exemplary compounds having formula I include:
  • X is N or CR 37 ;
  • R 21 -R 34 independently are selected from hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
  • R 35 is aliphatic, D- aliphatic, heteroaliphatic or D-heteroaliphatic;
  • R 36 is hydrogen, aliphatic, D-aliphatic,
  • R 37 is hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic.
  • at least one of R 21 -R 35 and R 37 is or comprises deuterium, and in certain embodiments, at least one of R 21 -R 35 is or comprises deuterium.
  • R 21 -R 37 is -R x -L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S; R x3 is selected from H, aliphatic, or aryl; L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ; R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, -C(0)OR x6 , or -C(0)NR x6 R x7 ; R x6 and R x7 are each independently selected from H, aliphatic; R x2 is selected from -C(0)L x2 R x8 or a carboxyl bioisostere; L x2 is a bond or NR x3 ; R x8 is H, aliphatic, -OR x
  • R 35 is alkyl, cycloalkyl, deuterated alkyl or deuterated cycloalkyl. In certain disclosed embodiments, R 35 is cycloalkyl or deuterated cycloalkyl, typically cyclohexyl or deuterated cyclohexyl, having from 1 to 11 deuterium atoms.
  • R 36 is hydrogen
  • R 32 is carboxyl and/or R 34 is CF3.
  • R 23 is halogen, and in certain embodiments R 23 is chloro.
  • the compound is chiral, and in certain embodiments, the compound is the 5-stereoisomer.
  • X is N, leading to compounds having a formula V
  • R 21 -R 36 is as defined above with respect to formula IV, and at least one of R comprises deuterium.
  • X is CH leading to compounds having formula VI
  • R 21 -R 36 is as defined above with respect to formula IV.
  • Exemplary compounds having formula IV include:
  • R 41 -R 48 and R 52 -R 55 independently are selected from hydrogen, deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
  • R 49 -R 51 independently are selected from hydrogen, deuterium, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
  • R 56 is amino, cycloamino or substituted cycloamino, such as 5-, 6-, or 7-membered cycloamino;
  • Y and Z are independently N or CR 57 ; and each R 57 independently is selected from deuterium, halogen, CF3, NO2, OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl,
  • aminosulfonyl aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic.
  • R 41 -R 57 is -R x -L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S; R x3 is selected from H, aliphatic, or aryl; L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ; R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, -C(0)OR x6 , or -C(0)NR x6 R x7 ; R x6 and R x7 are each independently selected from H, aliphatic; R x2 is selected from -C(0)L x2 R x8 or a carboxyl bioisostere; L x2 is a bond or NR x3 ; R x8 is H, aliphatic, -OR
  • At least one of R 41 -R 56 is or comprises deuterium.
  • R 51 is an aliphatic or D-aliphatic, and in certain embodiments, R 51 is a methyl or deuterated methyl, having from 1 to 3 deuterium atoms.
  • R 49 and R 50 independently are hydrogen or deuterium.
  • R 41 and R 45 independently are aliphatic or D-aliphatic, and in particular embodiments, R 41 and R 45 are methyl or deuterated methyl, having from 1 to 3 deuterium atoms.
  • R 56 is a cycloamino or substituted cycloamino, such as pyrrolidine, 2-methylpyrrolidine, morpholine, 4-methylpiperazine, piperidine, or azepane (homopiperidine).
  • Y is N and Z is N leadin to compounds having a formula VIII
  • Y is CH and Z is CH leadin to compounds having a formula IX
  • Y is N and Z is CH leadin to compounds having a formula X
  • R 41 -R 56 are as defined for formula VII.
  • Exemplary compounds having formula VII include:
  • R 105 and R 106 are each independently H, D, halogen, alkyl or deuterated alkyl
  • R 107 and R 108 are each independently H, D, alkyl, deuterated alkyl or halogen.
  • at least one of R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 and R 108 is or comprises deuterium.
  • at least one of R 105 , R 106 , R 107 and R 108 is or comprises deuterium.
  • at least one of R 107 and R 108 is halogen, and may be fluoro.
  • G 1 is CH or N; G 2 is O or NH; R 100 and R 101 are independently H, lower alkyl, halogen, or CF3; R 102 is lower alkyl; R 103 and R 104 are independently H, lower alkyl, halogen, CF3, OH, O-alkyl, or O-polyhaloalkyl.
  • R 205 is selected from the group consisting of COOR 210 , CONR 211 R 212 , tetrazolyl,
  • R 206 is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of OH, O-Ci-6 alkyl, O-halo-Ci-6 alkyl, Ci-6 alkyl, halo-Ci-6 alkyl, C3-6 cycloalkyl, D and halogen;
  • R 207 is selected from N or CH;
  • R 208 is selected from the group consisting of phenyl, pyridyl, thiazolyl, thiophenyl, pyrimidyl, each optionally substituted with one or two groups independently selected from the group consisting of D, Ci-6 alkyl, halo-Ci-6 alkyl, halogen and CF3;
  • R 209 is selected from
  • R 214 CH, N, NO, CD
  • R 215 is selected from the group consisting of hydrogen, C1-3 alkyl, C3.6 cylcoalkyl,
  • C4.5 alkylcycloalkyl wherein C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy or Ci-6 alkoxy;
  • R 216 and R 217 are independently selected from the group consisting of hydrogen, D, Ci- 3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, D-aliphatic and halogen.
  • R 218 and R 219 are each independently H or D. In some embodiments, R 218 and R 219 are both H. In other embodiments, at least one of R 218 and R 219 is D.
  • the compound comprises at least one deuterium.
  • R 206 and/or R 208 comprise at least one deuterium.
  • R 214 is CD.
  • at least one of R 216 and R 217 is or comprises deuterium.
  • R 205 -R 206 is selected from
  • Exemplary compounds having formula XIV include:
  • R 318 is selected from the group consisting of COOR 322 , CONR 323 R 324 , tetrazolyl or H, with R 322 independently selected from the group consisting of H, or lower alkyl, and R 323 and R 324 independently from each other selected from the group consisting of H, lower alkyl, Ci-6 haloalkyl, Ci-6 alkylene-R 325 , SO2-C1-6 alkyl wherein R 325 is selected from the group consisting of COOH,
  • R 319 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of OH, lower alkyl, lower cycloalkyl, or halogen;
  • R 320 is selected from the group consisting of phenyl, pyridyl, thiazolyl, thiophenyl, pyrimidyl, each optionally substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, D or CF3;
  • R 326 is CH, N, NO;
  • R327 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cylcoalkyl, C 4 - C5 alkylcycloalkyl, wherein C1-3 alkyl is optionally substituted with 1 to 3 substituents
  • R 328 and R 329 are independently selected from the group consisting of hydrogen, Ci- C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and halogen.
  • R 334 and R 335 are each independently H or D. In some embodiments, at least one of R 334 and R 335 are D.
  • R 320 is substituted with at least one halogen or deuterium.
  • R 318 is selected from the group consisting of COOR 322 , CONR 323 R 324 , tetrazolyl or H, with R 322 , R 323 and R 324 independently selected from the group consisting of H, lower alkyl;
  • R 319 is selected from the group consisting of phenyl, pyridyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of OH, lower alkyl, lower cycloalkyl;
  • R 320 is selected from the group consisting of phenyl, pyridyl, thiazolyl, thiophenyl, pyrimidyl, each optionally substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, D or CF3;
  • R 326 is CH, N, NO;
  • R 327 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3 C 6 cylcoalkyl, C4-C5 alkylcycloalkyl;
  • R 328 and R 329 are independently selected from the group consisting of hydrogen, Ci- C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and halogen.
  • compounds having formula XV may also have formula XVI
  • compounds having formula XV may also have the formula XVII,
  • R 332 is CH, CD or N;
  • R 330 and R 331 are independently selected from the group consisting of H, D, lower alkyl, halogen and CF3;
  • R 318 -R 319 is selected from
  • R 327 is selected from the group consisting of isopropyl, t-butyl and cyclopropyl;
  • R 328 and R 329 are independently selected from the group consisting of halogen, C1-C3 alkyl, methoxy and trifluoromethoxy;
  • R 334 and R 335 are each independently H or D. In some embodiments, at least one of R 334 and R 335 are D.
  • R 320 is optionally substituted phenyl, preferably substituted with one substituent, preferably halogen, or two substituents, preferably both halogen or one halogen one deuterium;
  • R 326 is CH
  • R 327 is cycloalkyl
  • R 328 and R 329 each are halogen.
  • Exemplary compounds having formula XV, XVI or XVII include:
  • kits that include any FXR agonist (or composition containing such an agonist) described herein and a device for localized delivery within a region of the intestines, such as the ileum or colon.
  • the device is a syringe, bag, or a pressurized container.
  • compositions comprising at least one compound having formulas I-III.
  • Pharmaceutical compositions comprising at least one of the disclosed compounds can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition may depend, for example, on the mode of administration (e.g., oral).
  • disclosed pharmaceutical compositions include a pharmaceutically acceptable carrier in addition to at least one or two or more active ingredients, such as a compound or compounds disclosed herein.
  • one or more of the disclosed compounds can be formulated with one or more of (such as 1, 2, 3, 4, or 5 of) an antibiotic (e.g., metronidazole, vancomycin, and/or fidaxomicin), statin, alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or dutoglpitin), meglitinide, sulfonylurea, peroxisome proliferator-activated receptor (PPAR)-
  • an antibiotic e.g., metronidazole, vancomycin, and/or fidaxomicin
  • statin e.g., metronidazole, vancomycin, and/or fida
  • compositions e.g., powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, without limitation, pharmaceutical grades of sugars, such as mannitol or lactose, polysaccharides, such as starch, or salts of organic acids, such as magnesium stearate.
  • pharmaceutical compositions can optionally contain amounts of auxiliary substances (e.g. , excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like; for example, sodium acetate or sorbitan monolaurate.
  • non- limiting excipients include nonionic solubilizers, such as cremophor, or proteins, such as human serum albumin or plasma preparations.
  • the pharmaceutical composition comprises a sufficient amount of a disclosed compound to have a desired therapeutic effect.
  • the disclosed compound constitutes greater than 0% to less than 100% of the pharmaceutical composition, such as 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, or 90% to less than 100% of the pharmaceutical composition.
  • compositions may be formulated as a pharmaceutically acceptable salt, solvate, hydrate, N-oxide or combination thereof, of a disclosed compound.
  • the pharmaceutical composition may comprise one or more polymorph of the disclosed compound.
  • Pharmaceutically acceptable salts are salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydriodic acid, and phosphoric acid.
  • Non-limiting examples of suitable organic acids include acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicylic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, and the like. Examples of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.
  • the compounds disclosed herein may be formulated to have a suitable particle size.
  • a suitable particle size may be one which reduces or substantially precludes separation of the components of the composition, e.g. , no separation between the drug and any other components of the composition, such as a second drug, a pharmaceutically acceptable excipient, a corticosteroid, an antibiotic or any combination thereof. Additionally, the particle size may be selected to ensure the composition is suitable for delivery, such as oral delivery.
  • the composition further includes an enteric coating.
  • an enteric coating is a polymer barrier applied to an oral medication to help protect the drug from the acidity and/or enzymes of the stomach, esophagus and/or mouth.
  • this coating can reduce or substantially prevent systemic delivery of the disclosed compound, thereby allowing substantially selective delivery to the intestines.
  • the enteric coating will not dissolve in the acid environment of the stomach, which has an acidic, pH of about 3, but will dissolve in the alkaline environments of the small intestine, with, for example, a pH of about 7 to 9.
  • Materials used for enteric coating include, but are not limited to, fatty acids, waxes, shellac, plastics and plant fibers.
  • the coating may comprise methyl acrylate- methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, or any combination thereof.
  • an indole acetonitrile 1 is treated with a suitable protecting group.
  • Scheme 1 illustrates using di-feri-butyl dicarbonate, in the presence of a base and in a suitable solvent, to form a BOC-protected indole (not shown).
  • Suitable solvents include, but are not limited to, aprotic solvents, such as dichloromethane, dichloroethane, THF, chloroform, or combinations thereof.
  • Suitable bases include, but are not limited to, triethylamine, 4- dimethylaminopyridine (DMAP), diiospropylethylamine, or combinations thereof.
  • the BOC- protected indole is further reacted with lithium bis(trimethylsilyl)amide (LiHMDS) in a suitable, aprotic solvent such as THF or ether, and at a temperature effective to facilitate a reaction, to form compound 2.
  • the effective temperature is from about -100 °C to about -50 °C, such as from about -80 °C to about -60 °C.
  • a suitable alkyl halide is then added to the reaction mixture, and the reaction mixture is warmed, or allowed to warm, to room temperature, such as to from about 20 °C to 25 °C.
  • alkyl portion of the alkyl halide will correspond to the desired R a and/or R b group.
  • R a and/or R b is methyl
  • a suitable alkyl halide may be methyl iodide.
  • R a and R b are alkyl
  • an excess of LiHMDS and alkyl halide are used in the reaction, such as about 2.5 equivalents.
  • only one of R a or R b is alkyl, and the other is hydrogen, then only 1 equivalent of LiHMDS and alkyl halide is used.
  • Compound 2 is then deprotected, such as by removal of the BOC group, to form the deprotected indole compound (not shown).
  • Suitable deprotection methods are known to persons of ordinary skill in the art and typically include reacting with an acid or acidic solution, including, but not limited to, trifluoroacetic acid or hydrochloric acid.
  • the cyano group on the deprotected indole compound is then reduced by a suitable reducing agent, such as lithium aluminum hydride (LAH, L1AIH4), at a temperature effective to facilitate a reaction, to form compound 3.
  • Suitable solvents for the reduction reaction include any aprotic solvent that will not react with the reducing agent, such as THF and ethers.
  • the effective temperature is from about 20 °C to greater than 100 °C, such as from about 40 °C to about 80 °C.
  • Compound 3 is then reacted with a halopyruvate, such as R c -bromopyruvate, where R c is the desired ester.
  • a halopyruvate such as R c -bromopyruvate, where R c is the desired ester.
  • the reaction is conducted in the presence of an acid, and in a suitable solvent and at an effective temperature, to form compound 4.
  • exemplary bromopyruvates include ethyl bromopyruvate and isopropyl bromopyruvate.
  • Suitable acids include aqueous acid such as hydrochloric acid.
  • Suitable solvents include protic solvents, such as alcohols.
  • ethanol is used as the solvent.
  • the effective temperature is from about 20 °C to greater than 100 °C, such as from about 50 °C to about 80 °C.
  • Compound 4 is then reacted with a base at a temperature effective to form compound 5.
  • Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, pyridine or combinations thereof.
  • the effective temperature is from about 20 °C to greater than 120 °C, such as from about 50 °C to about 110 °C.
  • Compound 5 is then reacted with a suitable acid or activated acid derivative, such as an acid chloride, to form the desired compound 6.
  • a suitable solvent include, but are not limited to, halogenated solvents such as chloroform, dichloroethane and dichloromethane, aprotic solvents such as DMF, DMSO, THF, acetonitrile, pyridine, toluene, or combinations thereof.
  • Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate or sodium hydrogen carbonate.
  • the reaction is conducted at a temperature effective to facilitate a reaction. In some embodiments, the effective temperature is from greater than 20 °C to greater than 120 °C, such as from about 50 °C to about 100 °C.
  • Scheme 2 Another exemplary embodiment of a general method of making a compound having formula I is shown in Scheme 2. This method is a modification of the method disclosed by Wang, et al. Tetrahedron Letters, 2011, 52, 3295-3297, which is incorporated herein in its entirety.
  • a pyrroloindoline 7 is reacted with an acetylene ester 8 in a suitable solvent, and at a temperature effective to facilitate a reaction, to form compound 9.
  • the reaction is performed under an inert atmosphere, such as nitrogen or argon.
  • Suitable solvents include, but are not limited to, polar, aprotic solvents such as DMF, DMSO or acetonitrile.
  • the effective temperature is from greater than 0 °C to greater than about 100 °C, such as from about 10 °C to about 50 °C, or about 20 °C to about 30 °C.
  • the reaction proceeds in the presence of a catalyst.
  • Suitable catalysts include, but are not limited to, copper halides, such as copper iodide, copper bromide, or copper chloride, salts of vitamin C such as sodium salt, potassium salt or lithium salt, or combinations thereof.
  • R e can be hydrogen or methyl.
  • compound 9 is demethylated prior to acylation (not shown).
  • the demethylation can be performed by any suitable method such as by reacting the tertiary amine with 1- chloroethylchloroformate in a suitable solvent.
  • Solvents suitable for the demethylation include, but are not limited to, halogenated solvents such as dichloromethane, dichloroethane and chloroform, or THF.
  • the reaction mixture is evaporated and then heated with an alcohol such as methanol for a time effective to form the secondary amine.
  • the effective time is from greater than 1 minute to greater than 1 hour, such as from about 10 minutes to about 30 minutes.
  • Compound 9, or the demethylated compound 9, is then reacted with a suitable acid or activated acid derivative, such as an acid chloride, to form the desired compound 10.
  • a suitable acid or activated acid derivative such as an acid chloride
  • the reaction is conducted in a suitable solvent, and in the presence of a suitable base.
  • suitable solvents include, but are not limited to, halogenated solvents such as chloroform, dichloroethane and
  • Suitable bases include, but are not limited to, triethylamine,
  • the reaction is conducted at a temperature effective to facilitate a reaction.
  • the effective temperature is from greater than 20 °C to greater than 120 °C, such as from about 50 °C to about 100 °C.
  • Scheme 3 One exemplary embodiment of a method of making a compound having formula IV is shown in Scheme 3. A person of ordinary skill in the art will appreciate that other suitable methods for making compounds having formula IV can be determined.
  • a protected diamine 21, such as a BOC-protected diamine is reacted with an aldehyde 22 in a suitable solvent for from about 10 minutes to greater than 60 minutes, such as from about 20 minutes to about 40 minutes.
  • suitable solvents include, but are not limited to, alcohols, such as methanol or ethanol, water or polar, aprotic solvents such as DMF or DMSO, or combinations thereof.
  • Acid 23 and isocyanide 24 are then added. After an amount of time effective to allow the reaction to proceed, the resulting product is deprotected, such as by adding a suitable acid 25 for removing the BOC protecting group.
  • the effective amount of time is from about 30 minutes to greater than 12 hours, such as from about 1 hour to about 4 hours.
  • Suitable acids are those known to a person of ordinary skill in the art to remove the protecting group, and include, but are not limited to, hydrochloric acid and trifluoroacetic acid.
  • the reaction mixture is left for an amount of time effective to facilitate a reaction to form compound 26, such as from about 6 hours to greater than 24 hours, such as from about 12 hours to about 20 hours.
  • the reaction mixture is agitated, such as by stirring or shaking, for at least some of the reaction time, and in some embodiments, for substantially all of the reaction time.
  • the reaction is conducted at a temperature effective to facilitate a reaction, such as from about 10 °C to greater than about 50 °C, typically from about 20 °C to about 40 °C.
  • Scheme 4 Another exemplary method of making a compound having formula IV is shown in Scheme 4. The method is a modification of the method disclosed in WO2004087714, which is incorporated herein in its entirety.
  • a haloindole 27, such as a bromo indole, is reacted with an ester compound 27a, which comprises a desired R group and a leaving group LG, to form compound 28.
  • the leaving group can be any suitable leaving group, such as a halide, triflate, mesalate or tosylate.
  • the reaction is performed in the presence of a base, such as sodium hydride, and in a suitable solvent, such as DMF or THF.
  • Compound 28 is typically saponified to an acid (not shown) by any suitable method known to a person of ordinary skill in the art, such as by reacting the acid with a hydroxide base, or by treatment with an aqueous acid, such as hydrochloric acid.
  • the acid is then typically activated, such as by forming an acid chloride, and then reacted with aniline to form compound 29.
  • the reaction is conducted in a suitable solvent, and in the presence of a suitable base.
  • Suitable solvents include, but are not limited to, halogenated solvents such as chloroform, dichloroethane and dichloromethane, aprotic solvents such as DMF, DMSO, THF, acetonitrile, pyridine, toluene, or combinations thereof.
  • Suitable bases include, but are not limited to, triethylamine,
  • the reaction is conducted at a temperature effective to facilitate a reaction.
  • the effective temperature is from greater than 20 °C to greater than 120 °C, such as from about 50 °C to about 100 °C.
  • Compound 29 is then reacted with a boronic acid (not shown) in a Suzuki-type coupling to form compound 30.
  • the boronic acid is an aromatic boronic acid.
  • the coupling is performed in the presence of a catalyst effective to facilitate the coupling reaction, and optionally in the presence of one or more additional compounds.
  • Typical catalysts for a Suzuki coupling are palladium or nickel catalysts, including but not limited to,
  • Typical additional compounds include, but are not limited to, triphenylphosphine (PPI13), and/or bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, sodium ethoxide, sodium methoxide, tripotassium phosphate or any combination thereof.
  • the coupling reaction is performed in any suitable solvent, such as DMF, ethanol, methanol, isopropanol, propanol, benzene, toluene, THF, dioxane, water or any combination thereof.
  • an amine 31 is reacted with an aldehyde 32.
  • the reaction typically is conducted in a suitable solvent, such as an alcohol, such as methanol or ethanol, water, or polar, aprotic solvents such as DMF or DMSO, or combinations thereof, for from about 10 minutes to greater than 60 minutes, such as from about 20 minutes to about 40 minutes.
  • An isocyanide 33 and a suitable azide 34 are then added, and the reaction mixture is left for an amount of time effective to facilitate a reaction to form compound 35, such as from about 6 hours to greater than 48 hours, such as from about 12 hours to about 24 hours.
  • One possible suitable azide is trimethylsilyl azide.
  • Scheme 6 provides one possible reaction mechanism for the reaction described in Scheme 5.
  • the amine 31 reacts with the aldehyde 32 with the loss of water, to form an imine 36.
  • the imine 36 then reacts with the isocyanide 33 to form an intermediate 37, which then reacts with the azide compound 34, to form an intermediate 38.
  • the intermediate 38 then cyclizes to form the desired compound 35.
  • Scheme 7 Another exemplary embodiment of a method of making a compound having formula VII is shown in Scheme 7. The method is a modification of the method disclosed by Chen, et al.
  • an aromatic halide compound 40 is reacted with an imidazole compound 41 in the presence of a copper catalyst, such as copper (I) bromide and an additional compound 42.
  • a copper catalyst such as copper (I) bromide and an additional compound 42.
  • the reaction is performed in a suitable solvent and in the presence of a suitable base.
  • suitable solvents include aprotic solvents such as DMSO or DMF.
  • Suitable bases include any base that will facilitate the reaction, such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate.
  • the reaction is conducted at a temperature effective to facilitate a reaction. In some embodiments, the effective temperature is from greater than 20 °C to greater than 120 °C, such as from about 50 °C to about 80 °C.
  • Fex Orally delivered fexaramine (Fex) (Downes et al, Mol Cell 11 : 1079-1092, 2003) is poorly absorbed, resulting in intestinally-restricted FXR activation. It is shown herein that despite this restricted activation, Fex treatment of diet-induced obesity (DIO) mice produces a novel metabolic profile that includes reduced weight gain, decreased inflammation, browning of white adipose tissue and increased insulin sensitization. The beneficial systemic efficacy achieved with Fex suggests intestinal FXR therapy as a potentially safer approach in the treatment of insulin resistance and metabolic syndrome.
  • DIO diet-induced obesity
  • the gut-biased FXR agonist fexaramine has profound metabolic benefits in a mouse model of obesity. Fex protects against diet- induced weight gain by promoting the expression of genes involved in thermogenesis, mitochondrial biogenesis, and fatty acid oxidation. Linked to the unexpected browning of white adipose, Fex lowers inflammatory cytokine levels while up-regulating ⁇ -adrenergic signaling. These changes appear to be mediated in part by a change in bile acid levels and composition. In addition, intestinal-specific FXR activation corrected numerous obesity-related defects, enhanced glucose tolerance, and lowered hepatic glucose production. Notably, these physiologic changes are dependent on FXR expression and result in hepatic insulin sensitization and BAT activation, properties not formerly associated with this class of drug.
  • intestinal FXR has been recently identified as a molecular target of vertical sleeve gastrectomy (Ryan et al, Nature 509:183-188, 2014), indicating that Fex may offer a non-surgical alternative for the control of metabolic disease.
  • Treatment of subjects, including diet- induced obesity (DIO) subjects, with one or more of the disclosed FXR agonists (such as two or more, three or more, four or more, or five or more of the disclosed FXR agonists, such as 2, 3, 4, or 5 of the disclosed FXR agonists) may produce beneficial body-wide metabolic effects such as reduced weight gain, decreased inflammation, browning of white adipose tissue, activation of BAT, improved insulin sensitization, or combinations thereof.
  • intestinally-restricted FXR administration is superior to systemic FXR therapy for body- wide metabolic disorders including obesity and metabolic syndrome.
  • One or more of the FXR agonists disclosed herein may be administered to a gastrointestinal (GI) tract of the subject to activate FXR receptors in the intestines, and thereby treat or prevent a metabolic disorder in the subject.
  • GI gastrointestinal
  • the FXR agonist(s) can be administered to, without limitation, the mouth (such as by injection or by ingestion by the subject), the esophagus, the stomach or the intestines themselves.
  • these agonists may in some examples be ineffectively absorbed, resulting in intestinally-restricted FXR activation.
  • FXR activation is completely limited to the intestine.
  • administration of one or more of the disclosed agonists does not result in significant activation in the liver or kidney.
  • some measurable extra-intestinal FXR activation occurs, however the FXR activation is considerably greater in the intestines than in other locations in the body, such as in the liver or kidney.
  • the FXR agonist is minimally absorbed.
  • the FXR agonist is directly administered to the intestines (such as to the distal ileum) of an individual in need thereof.
  • the FXR agonist is directly administered to the colon or the rectum of an individual in need thereof. In some embodiments, the FXR agonist is administered orally, and less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the FXR agonist is systemically absorbed.
  • the subject to be treated is one who is diabetic (for example has type II diabetes), is hyperglycemic, and/or is insulin resistant.
  • the subject is obese, for example has a body mass index (BMI) of 25 of higher, 30 or greater, 35 or greater, 40 or greater, such as a BMI of 25 to 29, 30 to 34, or 35 to 40.
  • BMI body mass index
  • the disclosed methods may reduce weight gain in a subject (such as a human), such as diet-induced weight gain.
  • a subject such as a human
  • such methods reduce weight gain in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed methods reduce the BMI of a subject (such as a human).
  • such methods reduce the BMI of a subject by at least 5%, at least 10%, at least 15%, at least 20%, or at least 30% (such as 5% to 30%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed methods may increase browning of white adipose tissue in a subject (such as a human). In some examples, such methods increase browning of white adipose tissue in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the method may reduce or prevent diet-induced weight gain, for example in a mammalian subject, such as a human.
  • the one or more FXR agonists are administered to an obese subject whose obesity is diet-related (i.e., diet-induced obesity).
  • the one or more FXR agonists can be administered to an obese subject whose obesity is not diet-related (such as an individual with familial/genetic obesity or obesity resulting from medication use).
  • the one or more FXR agonists can be administered to a subject who is overweight (but not obese) or a subject that is neither overweight nor obese.
  • the one or more FXR agonists can be used to prevent obesity from developing.
  • the targeting of the therapy to the intestines reduces the chance of side effects which can result from systemic action, thus improving the safety profile of the therapy.
  • the one or more FXR agonists are administered to an obese or non- obese subject for a metabolic disorder or condition other than obesity or weight gain.
  • the metabolic disorder is insulin resistance, including non-insulin-dependent diabetes mellitus (NIDDM) (i.e. , type II diabetes).
  • NIDDM non-insulin-dependent diabetes mellitus
  • the administration of the one or more FXR agonists can result in increased insulin sensitivity to insulin in the liver, leading to increased uptake of glucose into hepatic cells.
  • the metabolic disorder is dyslipidemia, including hyperlipidemia (elevated LDL, VLDL or triglycerides) or low HDL levels.
  • administration of one or more FXR agonists can result in improved glucose and/or lipid homeostasis in the subject.
  • administration of the one or more FXR agonists results in a decrease in the amount of serum lipids and/or triglycerides, decrease liver free fatty acids, decrease liver cholesterol, increase liver glycogen, decrease muscle free fatty acids, decrease muscle cholesterol, or combinations thereof, in the subject.
  • the disclosed methods decrease the amount of serum lipids and/or triglycerides in a subject (such as a human).
  • such methods decrease serum lipids and/or triglycerides in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • such methods decrease liver free fatty acids in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • such methods decrease liver cholesterol in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • such methods increase liver glycogen in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 90%, at least 100%, or at least 200% (such as 5% to 50%, 5% to 25%, 100% to 200%, 10% to 100%, or 10% to 200%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • such methods decrease muscle free fatty acids in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • such methods decrease muscle cholesterol in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • the disclosed embodiments may increase insulin sensitivity to insulin in the liver of a subject (such as a human).
  • such methods increase insulin sensitivity to insulin in the liver of the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • administration of the one or more FXR agonists results in no substantial change in food intake and/or fat consumption in the subject.
  • food intake and/or fat consumption is reduced minimally, such as by less than 15%, less than 10%, or less than 5%.
  • no substantial change in appetite in the subject results.
  • reduction in appetite is minimal as reported by the subject.
  • administration of the one or more FXR agonists results in an increase in the metabolic rate in the subject.
  • the disclosed methods may increase the metabolic rate in a subject (such as a human).
  • such methods increase the metabolic rate in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • this increase in metabolism results from enhanced oxidative phosphorylation in the subject, which in turn can lead to increased energy expenditure in tissues (such as BAT).
  • the disclosed methods may increase BAT activity in a subject (such as a human).
  • such methods increase BAT activity in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • administration of the one or more FXR agonists results in a decrease in the amount of serum insulin in the subject.
  • the disclosed methods decrease the amount of serum insulin in a subject (such as a human).
  • such methods decrease serum insulin in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • administration of the one or more FXR agonists results in a decrease in the amount of serum glucose in the subject.
  • the disclosed methods decrease the amount of serum glucose in a subject (such as a human).
  • such methods decrease serum glucose in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to levels observed in a subject not treated with the disclosed therapies.
  • Embodiments of a method are provided for lowering elevations in blood glucose resulting from food intake in a subject.
  • such methods decrease blood glucose in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • Such methods can include orally administering to the subject a therapeutically effective amount of one of the disclosed minimally absorbed FXR agonists.
  • a method for lowering elevated body weight in a subject is provided, wherein the method includes orally administering to said subject a therapeutically effective amount of one of the disclosed minimally absorbed FXR agonists.
  • such methods decrease the body weight of a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 50% (such as 5% to 50%, 5% to 25%, 5% to 20%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the elevated body weight and/or elevated glucose levels resulted from a particular pattern of food intake, such as a high fat diet and/or a high calorie diet.
  • the one or more FXR agonists are co-administered with one or more additional compounds or therapies, for treatment or prevention of a metabolic disorder.
  • one or more FXR agonists can be administered with an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a glucagon-like peptide (GLP) agonist, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or dutoglpitin), a catecholamine (such as epinephrine, norepinephrine, or dopamine), peroxisome proliferator-activated receptor (PPAR)-gamma agonist (e.g., a thiazolidinedione (TZD) [such as
  • one or more FXR agonists can be administered with a statin, HMG-CoA reductase inhibitor, fish oil, fibrate, niacin or other treatment for dyslipidemia.
  • a method for treating a metabolic disorder in a subject comprising orally co-administering to said subject a
  • the method includes also administering nicotinamide ribonucleoside and/or an analog of nicotinamide ribonucleoside (such as those that promote NAD+ production of which is a substrate for many enzymatic reactions such as p450s which are a target of FXR, for example see Yang et al., J. Med Chem. 50:6458-61, 2007, herein incorporated by reference).
  • GLP-1 Glucagon-like peptide- 1
  • GLP-1 is an incretin derived from the transcription product of the proglucagon gene.
  • the major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone.
  • the biologically active forms of GLP-1 include GLP-1 -(7-37) and GLP- l-(7-36)NH 2 (HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 1), which result from selective cleavage of the proglucagon molecule.
  • GLP-2 is a 33 amino acid peptide
  • GLP-2 is created by specific post-translational proteolytic cleavage of proglucagon in a process that also liberates GLP-1.
  • GLP agonists are a class of drugs ("incretin mimetics") that can be used to treattype 2 diabetes. Examples include, but are not limited to: exenatide (Byetta/Bydureon), liraglutide (Victoza), lixisenatide (Lyxumia), and albiglutide (Tanzeum).
  • the FXR agonist enhances the secretion of glucagon-like peptide- 1 (GLP-1) and/or glucagon-like peptide-2 (GLP-2). In some embodiments, the FXR agonist enhances the secretion of a pancreatic polypeptide-fold such as peptide YY (PYY). In certain embodiments, the FXR agonist enhances the activity of FGF15 or FGF19. In certain embodiments, the FXR agonist enhances secretion of an enteroendocrine peptide and/or is administered in combination with an agent that enhances secretion or activity of an enteroendocrine peptide.
  • the disclosed methods may increase the secretion of one or more of GLP-1, GLP-2, and PYY in a subject (such as a human).
  • a subject such as a human
  • such methods increase the secretion of one or more of GLP-1, GLP-2, and PYY in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed methods increase the secretion of one or more of GLP-1, GLP-2, and PYY in a subject (such as a human).
  • such methods increase the activity of one or more of FGF15 and FGF19 in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the gut-biased FXR agonists disclosed herein can have profound metabolic benefits with respect to obesity.
  • the gut-biased FXR agonists can protect against diet-induced weight gain by, for example, promoting the expression of genes involved in thermogenesis, mitochondrial biogenesis, and/or fatty acid oxidation.
  • the disclosed gut-biased FXR agonists linked to the unexpected browning of white adipose, can lower inflammatory cytokine levels while up-regulating ⁇ -adrenergic signaling. These changes can be mediated, at least in part, by a change in bile acid levels and composition.
  • a prandial activation of intestinal FXR is triggered by administering to a subject one of the FXR agonists disclosed herein, such as synthetic FXR agonist fexaramine (Fex).
  • the intestinal-specific FXR activation disclosed herein can be utilized to enhance glucose tolerance and lower hepatic glucose production.
  • such methods may decrease hepatic glucose production in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50% or even at least 75% (such as 5% to 50%, 5% to 25%, 10% to 20%, 10% to 70%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • These physiologic changes can result in hepatic insulin sensitization and/or BAT activation - properties not previously associated with FXR agonists.
  • intestinal FXR in contrast to the effects of system- wide drugs (including systemic FXR agonists), selective activation of intestinal FXR as disclosed herein can mimic the restricted bile acid response linked to feeding.
  • the FXR agonists disclosed herein may be gut-specific and robustly induce enteral FGF15, leading to alterations in bile acid composition without activating hepatic FXR target genes.
  • these gut-specific FXR agonists may protect against diet- induced weight gain, reduce body-wide inflammation, enhance thermogenesis, promote browning of white adipose tissue, promote activation of BAT, and suppress hepatic glucose production.
  • the initial event triggering systemic metabolic activation is coordinated by FGF15 (the mouse equivalent of human FGF19) or FGF19.
  • administration of the FXR agonist results in activation of FGF15 or FGF19 (such as an increase in FGF15 or FGF19 activity of at least 25%, at least 50%, at least 75%, at least 90%, or at least 95%, relative to no treatment with an FXR agonist), which in turn can regulate energy expenditure, such as by increasing metabolic rate, improving glucose homeostasis (such as by improving insulin sensitivity), and/or improving lipid homeostasis without requiring significant changes in food intake.
  • treatment with one or more of the disclosed FXR agonists can produce a change in the bile acid pool, such as a dramatic increase in the level of deoxycholic acid (such as an increase of at least 25%, at least 50%, at least 75%, at least 90%, or at least 100%, relative to no treatment with an FXR agonist), a potent ligand for the G protein-coupled bile acid receptor TGR5.
  • Fex treatment was observed to induce DI02, a downstream target of TGR5, in brown adipose tissue (BAT), thus implicating this additional pathway in the observed increase in energy expenditure.
  • the coordinate "browning" of white adipose tissue provides an independent yet complementary contribution to increased thermogenic capacity.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • the disclosed embodiments may reduce inflammation in a subject
  • such embodiments may reduce inflammation (such as intestinal inflammation) in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the inflammatory condition can be necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, pseudomembranous colitis, gastroenteritis, radiation induced enteritis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, gastrointestinal complications following bariatric surgery, gastric carcinogenesis, or gastric carcinogenesis following gastric or bowel resection.
  • NEC necrotizing enterocolitis
  • gastritis gastritis
  • ulcerative colitis inflammatory bowel disease
  • irritable bowel syndrome pseudomembranous colitis
  • gastroenteritis radiation induced enteritis
  • chemotherapy induced enteritis chemotherapy induced enteritis
  • GSD gastro-esophageal reflux disease
  • NUD non-ulcer dyspepsia
  • celiac disease intestinal celi
  • the inflammatory condition is NEC and the subject is a newborn or prematurely born infant. In some embodiments, the subject is enterally-fed infant or formula-fed infant.
  • the one or more FXR agonists are co-administered with one or more additional compounds or therapies, for treatment or prevention of an inflammatory intestinal condition. In some embodiments, the one or more FXR agonists are co-administered with an oral corticosteroid and/or other anti-inflammatory or immuno-modulatory therapy. In some
  • the FXR agonist can be administered to the subject in conjunction with one or more antibiotics (e.g., metronidazole, vancomycin, and/or fidaxomicin) to treat or prevent the inflammatory condition.
  • antibiotics e.g., metronidazole, vancomycin, and/or fidaxomicin
  • the FXR agonist can be administered to the subject in conjunction with or following antibiotic therapy to treat or prevent pseudomembranous colitis associated with bacterial overgrowth (such as C. pere overgrowth) in the subject.
  • the FXR agonist can be administered to the subject in conjunction with pseudomembranous colitis associated with bacterial overgrowth (such as C. percutaneous overgrowth) in the subject.
  • the FXR agonist can be administered to the subject in conjunction with
  • the FXR agonist can be administered to the subject in conjunction with the ingestion of foods or other substances predicted to induce inflammation in the gastro-intestinal system of the subject (such as in a subject with celiac disease).
  • the method includes also administering nicotinamide ribonucleoside and/or an analog of nicotinamide ribonucleoside (such as those that promote NAD+ production of which is a substrate for many enzymatic reactions such as p450s which are a target of FXR, for example see Yang et al., J. Med Chem. 50:6458-61, 2007, herein incorporated by reference).
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • the compounds disclosed herein may be used in the prevention or treatment of adenocarcinomas, i.e. carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • Adenocarcinomas can be classified according to the predominant pattern of cell arrangement, as papillary, alveolar, etc., or according to a particular product of the cells, as mucinous adenocarcinoma.
  • Adenocarcinomas arise in several tissues, including the colon, kidney, breast, cervix, esophagus, gastric, pancreas, prostate and lung.
  • the compounds disclosed herein may be used in the prevention or treatment of a cancer of the intestine, such as colon cancer, i.e. cancer that forms in the tissues of the colon (the longest part of the large intestine), or a cancer of another part of the intestine, such as the jejunum, and/or ileum.
  • Colon cancer is also referred to as "colorectal cancer.”
  • Most colon cancers are adenocarcinomas (cancers that begin in cells that may line internal organs and have gland-like properties). Cancer progression is characterized by stages, or the extent of cancer in the body. Staging is usually based on the size of the tumor, whether lymph nodes contain cancer, and whether the cancer has spread from the original site to other parts of the body.
  • Stages of colon cancer include stage I, stage II, stage III and stage IV.
  • the colon adenocarcinoma is from any stage.
  • the colon adenocarcinoma is a stage I cancer, a stage II cancer or a stage III cancer.
  • the disclosed embodiments reduce tumor burden in a subject (such as a human).
  • disclosed embodiments reduce tumor burden (such as colon tumor burden) in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce tumor size and/or volume in a subject (such as a human).
  • a subject such as a human
  • disclosed embodiments reduce tumor size and/or volume (such as a colon tumor) in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce effects of cachexia due to a tumor in a subject (such as a human).
  • disclosed embodiments reduce effects of cachexia (such as due to a colon tumor) in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments increase survival rates of a subject (such as a human) with a tumor.
  • disclosed embodiments increase survival rates of a subject (such as a human) with a tumor (such as a colon cancer) in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the compounds disclosed herein may be administered in combination with one or more additional anticancer therapies (such as a biologic [e.g., antibody, for example bevacizumab, cetuximab, or panitumumab], chemotherapeutic, or radiologic, for example
  • a biologic e.g., antibody, for example bevacizumab, cetuximab, or panitumumab
  • chemotherapeutic e.g., chemotherapeutic, or radiologic, for example
  • the method includes also administering nicotinamide ribonucleoside and/or an analog of nicotinamide ribonucleoside (such as those that promote NAD+ production of which is a substrate for many enzymatic reactions such as p450s which are a target of FXR, for example see Yang et al., J. Med Chem. 50:6458-61, 2007, herein incorporated by reference).
  • alcoholic or non-alcoholic liver diseases such as steatosis, cirrhosis, alcoholic hepatitis, NASH and NAFLD.
  • the compounds disclosed herein may be used in the prevention or treatment of alcoholic liver diseases.
  • Certain disclosed embodiments can include administering a
  • FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • the disclosed embodiments reduce fatty liver (steatosis) in a subject (such as a human).
  • a subject such as a human
  • disclosed embodiments reduce steatosis in the subject (such as in an alcoholic) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce cirrhosis in a subject (such as a human).
  • disclosed embodiments reduce cirrhosis in the subject (such as in an alcoholic) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments can reduce liver inflammation and/or fibrosis, for example by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce alcoholic hepatitis in a subject (such as a human).
  • disclosed embodiments reduce alcoholic hepatitis in the subject (such as in an alcoholic) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments can reduce inflammation of hepatocytes, for example by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce liver enzymes in a subject (such as a human).
  • disclosed embodiments reduce liver enzymes (e.g., serum ALT and/or AST levels) in the subject (such as in an alcoholic) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the disclosed embodiments reduce liver triglycerides in a subject (such as a human).
  • a subject such as a human
  • disclosed embodiments reduce liver triglycerides in the subject (such as in an alcoholic) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • the compounds disclosed herein may be administered in combination with one or more additional therapies for treating alcoholic or non-alcoholic liver disease (such as antioxidants, corticosteroids, and/or anti-TNF), to prevent or treat alcoholic or non-alcoholic liver disease.
  • additional therapies for treating alcoholic or non-alcoholic liver disease such as antioxidants, corticosteroids, and/or anti-TNF
  • ribonucleoside that promotes NAD+ production of which is a substrate for many enzymatic reactions such as p450s which are a target of FXR (e.g., see Yang et al., J. Med. Chem. 50:6458- 61, 2007), are also administered.
  • cholestatic disorders such primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), overlap syndrome (PBC plus autoimmune hepatitis), cholestasis resulting from a drug (e.g., one or more of androgen, birth control pills, gold salts, nitrofurantoin, anabolic steroids, chlorpromazine, prochlorperazine, sulindac, cimetidine, estrogen, statins, and antibiotics such as TMP/SMX, flucoxacillin and erythromycin), drug-induced cholestatic hepatitis, total parenteral nutrition (TPN)-induced cholestasis, ICU/sepsis-related cholestasis, obstetric cholestasis, graft vs.
  • a drug e.g., one or more of androgen, birth control pills, gold salts, nitrofurantoin, anabolic steroids, chlor
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • the disclosed embodiments increase bile flow in a subject (such as a human) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at last 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or even at least 200% (such as 5% to 50%, 5% to 25%, 50% to 75%, or 75% to 200%), for example relative to a subject not treated with the disclosed therapies.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • disclosed embodiments reduce undesired intestinal permeability in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • disclosed embodiments bring the intestinal microbiome closer to normal levels in the subject, for example within 20%, with in 10% or within 5% of normal for example relative to a subject not treated with the disclosed therapies.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • FXR agonists such as 1, 2, 3, 4 or 5 such agonists.
  • disclosed embodiments reduce plasma cholesterol levels in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • a method for treating a bile disorder such as benign biliary stricture, malignant biliary obstruction, bile acid diarrhea, or any combination thereof.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • FXR agonists such as 1, 2, 3, 4 or 5 such agonists.
  • disclosed embodiments reduce production of bile acids in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% or even at least 50% (such as 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%), for example relative to a subject not treated with the disclosed therapies.
  • disclosed embodiments increase intestinal absorption of bile acids in the subject by at least 5%, at least 10%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at last 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or even at least 200% (such as 5% to 50%, 5% to 25%, 50% to 75%, or 75% to 200%), for example relative to a subject not treated with the disclosed therapies.
  • a malabsorption disorder e.g., intestinal malabsorption
  • short bowel syndrome or symptoms arising from such, such as diarrhea, steatorhea, malnutrition, fatigue, vitamin deficiency), environmental enteropathy, or tropical sprue.
  • Certain disclosed embodiments can include administering a therapeutically effective amount of one or more FXR agonists to an individual in need thereof, such as one or more of the novel FXR agonists disclosed herein (such as 1, 2, 3, 4 or 5 such agonists).
  • disclosed embodiments increase bowel absorption in the subject by at least 5%, at least 10%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at last 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or even at least 200% (such as 5% to 50%, 5% to 25%, 50% to 75%, or 75% to 200%), for example relative to a subject not treated with the disclosed therapies.
  • Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.
  • a therapeutically effective amount of one or more compounds disclosed herein can be administered in a single dose, twice daily, weekly, or in several doses, for example daily, or during a course of treatment.
  • treatment involves once daily dose or twice daily dose.
  • the FXR agonist(s) is administered orally.
  • the FXR agonist is administered as an ileal-pH sensitive release formulation that delivers the FXR agonist to the intestines, such as to the ileum of an individual.
  • the FXR agonist is administered as an enterically coated formulation.
  • oral delivery of an FXR agonist provided herein can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.
  • enteric -coated and enteric-coated controlled release formulations are within the scope of the present disclosure.
  • Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
  • the FXR agonist is administered before ingestion of food, such as at least 10 minutes, at least 15 minutes, at least 20 minutes, or at least 30 minutes before ingestion of food (such as 10-60 minutes or 10-30 minutes before ingesting food). In some embodiments of the methods described herein, the FXR agonist is administered less than about 60 minutes before ingestion of food. In some embodiments of the methods described above, the FXR agonist is administered less than about 30 minutes before ingestion of food. In some embodiments of the methods described herein, the FXR agonist is administered after ingestion of food.
  • the methods further comprise administration of a DPP-IV inhibitor, a TGR5 agonist, a biguanide, an incretin mimetic, or GLP- 1 or an analog thereof.
  • the methods further comprise administration of a steroid or other anti-inflammatory compound which may have an effect in the gut.
  • the methods further include co- administration of an antibiotic therapy, and the FXR agonist treats or prevents inflammation, such as inflammation associated with antibiotic-induced colitis.
  • composition administered can include at least one of a spreading agent or a wetting agent.
  • the absorption inhibitor is a mucoadhesive agent (e.g., a
  • a pharmaceutical composition administered further includes an enteroendocrine peptide and/or an agent that enhances secretion or activity of an enteroendocrine peptide.
  • a unit dosage contains from about 1 mg to about 50 g of one or more compounds disclosed herein, such as about 10 mg to about 10 g, about 100 mg to about 10 g, about 100 mg to about 1 g, about 500 mg to about 5 g, or about 500 mg to about 1 g.
  • a therapeutically effective amount of one or more compounds disclosed herein is from about 0.01 mg/kg to about 500 mg/kg, for example, about 0.5 mg/kg to about 500 mg/kg, about 5 mg/kg to about 250 mg/kg, or about 50 mg/kg to about 100 mg/kg.
  • a therapeutically effective amount of one or more compounds disclosed herein is from about 50 mg/kg to about 250 mg/kg, for example about 100 mg/kg.
  • Fexaramine prevents diet-induced obesity weight gain
  • mice were subjected to chronic fexaramine (100 mg/kg Fex) PO treatment for 5 weeks.
  • Chronically treated chow-fed mice were indistinguishable from vehicle-treated mice in terms of weight gain, basal metabolic activity and glucose tolerance (FIGS. 3A-3D).
  • fexaramine Serum levels of inflammatory cytokines TNFoc, IL-loc, IL- ⁇ , IL-17 and MCP-1 were markedly decreased by fexaramine (FIG. 2E) (such as reductions of at least 50%, at least 75%, at least 80%, or even at least 90%), indicating that fexaramine-induced weight gain resistance reduced systemic inflammation.
  • the reduction in fasting insulin levels also suggested improved glucose tolerance and insulin sensitivity in fexaramine-treated DIO mice. Therefore, glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) were performed to determine if glucose homeostasis was improved in fexaramine-treated DIO mice.
  • Fex treatment induced dose-dependent improvements in glucose tolerance and insulin sensitivity in DIO mice (measured by glucose and insulin tolerance tests) (FIGS. 2F and 2G and 4C).
  • fexaramine improved glucose homeostasis in a dose-dependent manner in DIO mice
  • these Fex-induced changes in gene expression and improvements in metabolic homeostasis were abrogated in Fex-treated FXR null mice, establishing the FXR dependence of the observed effects (FIGS. 5A-5I).
  • Fexaramine enhances energy expenditure in brown adipose tissue
  • Fex treatment increased the core body temperature approximately 1.5 °C (FIG. 6E).
  • BAT brown adipose tissue
  • Fex- treated mice FIG. 6F.
  • Gene expression analysis confirmed the induction of ERRy, PGC- ⁇ , and PGC- ⁇ , as well as a number of their target genes involved in thermogenesis, mitochondrial biogenesis, and fatty acid oxidation in BAT (FIG. 6G).
  • Fex treatment increased the phosphorylation level of p38 (FIG. 6H and 61), previously shown to stabilize PGC- ⁇ , a key coactivator of the thermogenic transcriptional program in BAT.
  • PPAR signaling pathway 7.53E-03 Furthermore, serum lactate levels were significantly reduced in Fex-treated DIO mice, suggesting that body-wide energy metabolism is shifted towards a more oxidative state (FIG. 6N). Thus, the marked reduction in lipids, increased PKA activity and p38 phosphorylation, and increased core body temperature indicate a coordinated activation of thermogenesis in BAT in Fex- treated DIO mice.
  • Fexaramine induces FGF15 and alters bile acid composition
  • RNA-Seq of intestinal tissues was used to explore the mechanisms through which Fex might contribute to systemic changes in energy expenditure and metabolic rate.
  • Mice were fed on HFD for 14 weeks, and then subjected to daily oral injection of vehicle or fexaramine (100 mg/kg) for 5 weeks with HFD.
  • KEGG pathway analysis revealed the induction of multiple cellular metabolic pathways including PPAR and adipocytokine signaling in both ileum and colon (Tables 2 and 3).
  • FGF15 induction is of interest since it activates the thermogenic program in BAT, as well as negatively regulate BA synthesis through suppression of hepatic CYP7A1, the rate-limiting enzyme for BA synthesis.
  • An increase in circulating FGF15 accompanied the increase in mRNA expression in ileum (FIGS. 7B and 7C) (such as an increase of at least 100%, at least 125%, or at least 150%).
  • hepatic CYP7A1 expression was significantly repressed at both the mRNA and protein level after chronic Fex treatment, while the expression of CYP8B 1 and CYP27A1 (enzymes not regulated by FGF15) were not affected (FIG.
  • T-UDCA 2.85 3.07 alpha MCA 0.33 N.D beta MCA 0.55 N.D
  • mice fed a HFD for 14 weeks were maintained on a HFD and treated with vehicle or fexaramine (lOOmg/kg/day per os for 5 week).
  • Serum bile acid composition was determined by mass spectrometry. N.D not determined.
  • mice showed reduced intestinal permeability, as measured by FITC-dextran leakage into the serum, and increased expression of mucosal defense genes Occludin and Muc2, after chronic Fex-treatment (FIGS. 7G and 7H).
  • TGR5 null mice were chronically treated with Fex (100 mg/kg/day PO for 5 weeks).
  • Fex treatment induced multiple FXR target genes in the ileum of TGR5 null mice including FGF15, resulting in lowered serum BA levels (FIGS. 11A, 11B).
  • Fex treatment induced moderate improvements in fasting glucose levels and glucose tolerance (FIGS. 11C, 11D).
  • FIGS. 11E-11H somewhat blunted increases in core body temperature and metabolic rate, correlating with the induction of thermogenic genes in BAT, were observed (FIGS. 11E-11H), indicating that these effects do not require TGR5 activation.
  • Fexaramine induces browning of white adipose tissue
  • adipose tissue expands by hyperplastic and/or hypertrophic growth, is chronically inflamed, and produces inflammatory cytokines that ultimately contribute to systemic metabolic dysregulation.
  • the cross-sectional area of adipocytes in visceral depots including gonadal and mesenteric was markedly reduced (FIG. 12A).
  • Investigation of signaling pathways implicated in diet-induced inflammation identified reduced levels of ⁇ - ⁇ and TANK-binding kinase 1 (TBK1) in Fex-treated DIO mice (FIGS. 12B, 13).
  • noncanonical ⁇ kinases were recently shown to play crucial roles in energy expenditure as a consequence of adipose tissue inflammation upon diet-induced obesity (Reilly et al, Nat Med 19:313-321, 2013).
  • mTORCl mammalian target of rapamycin complexl
  • HFD high fat diet
  • Brown adipose-driven adaptive thermogenesis is fueled by mitochondrial oxidation of free fatty acids (FFAs) released from triglyceride stores into the circulation predominantly by the action of hormone-sensitive lipase (HSL).
  • FFAs free fatty acids
  • HSL hormone-sensitive lipase
  • Fexaramine improves insulin sensitivity and glucose tolerance
  • HGP basal hepatic glucose production
  • GDR glucose disposal rate
  • IS-S insulin-stimulated GDR
  • liver insulin resistance has been linked to obesity-induced hepatic steatosis (Cohen et al., Science 332: 1519-1523, 2011). Histological examination of liver tissue from Fex-treated DIO mice revealed a reduction in lipid droplets compared to controls indicating amelioration of hepatic steatosis (FIG. 15E). Consistent with this histology, a marked decrease in hepatic triglycerides (such as a reduction of at least 10%, or at least 20%) and reduced hepatic expression of gluconeogenic and lipogenic genes (such as a reduction of at least 20%, or at least 30%, or at least 50%) were seen after chronic Fex treatment (FIGS.15F and 15G).
  • ALT serum alanine aminotransferase
  • FXR activity screen for determining ECso determination Cell Culture and Transfection: CV-1 cells were grown in DMEM+10% charcoal stripped FCS. Cells were seeded into 384-well plates the day before transfection to give a confluency of 50-80% at transfection. A total of 0.8 grams DNA containing 0.32 micrograms pCMX-hFXRfl, 0.32 micrograms pCMX-hRXRfl, 0.1 micrograms pCMX.beta.Gal, 0.08 micrograms pGLFXRE reporter and 0.02 micrograms pCMX empty vector was transfected per well using FuGene transfection reagent according to the manufacturer's instructions (Roche). Cells were allowed to express protein for 48 hours followed by addition of compound.
  • Plasmids Human FXR full length and RXR full length was obtained from Ronald Evans' laboratory and PCR amplification of the hFXR cDNA and the hRXR cDNA was performed. The amplified cDNAs was cloned into the vector pCMX generating the plasmids pCMX-hFXRfl and pCMX-hRXRfl. Ensuing fusions were verified by sequencing.
  • the pCMXMH2004 luciferase reporter contains multiple copies of the GAL4 DNA response element under a minimal eukaryotic promoter (Hollenberg and Evans, 1988). pCMX.beta.Gal was generated in the Evans laboratory, Salk Institute.
  • luciferase assay Medium including test compound was aspirated and washed with PBS. 50 ⁇ . PBS including 1 mM Mg 2+ and Ca 2+ were then added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission was quantified by counting on a Perkin Elmer Envision reader.
  • Beta-galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Perkin Elmer Envision reader. The beta-galactosidase data were used to normalize (transfection efficiency, cell growth etc.) the luciferase data.
  • Statistical Methods The activity of a compound is calculated as fold induction compared to an untreated sample. For each compound the efficacy (maximal activity) is given as a relative activity compared to Fexaramine, a FXR agonist. The EC50 is the concentration giving 50% of maximal observed activity. EC50 values were calculated via non- linear regression using GraphPad PRISM (GraphPad Software, San Diego, Calif.).

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Abstract

La présente invention se rapporte à de nouveaux agonistes de FXR, des modes de réalisation d'un procédé pour les produire et une composition les comprenant. L'invention concerne également des modes de réalisation d'un procédé de traitement ou de prévention d'un trouble métabolique chez un sujet, ledit procédé comprenant l'administration à un sujet (par exemple par voie gastro-intestinale) d'une quantité thérapeutiquement efficace d'un ou de plusieurs des composés selon l'invention, ce qui permet d'activer les récepteurs FXR dans les intestins, et le traitement ou la prévention d'un trouble métabolique chez le sujet. L'invention concerne en outre des modes de réalisation d'un procédé de traitement ou de prévention de l'inflammation dans une région intestinale d'un sujet, comprenant l'administration au sujet (par exemple par voie gastro-intestinale) d'une quantité thérapeutiquement efficace d'un ou de plusieurs des composés selon l'invention, ce qui permet d'activer des récepteurs FXR dans les intestins et, de ce fait, de traiter ou de prévenir l'inflammation dans la région intestinale du sujet.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10301268B2 (en) 2014-03-13 2019-05-28 The Salk Institute For Biological Studies Analogs of fexaramine and methods of making and using
WO2020042114A1 (fr) * 2018-08-30 2020-03-05 Terns Pharmaceuticals, Inc. Traitement de troubles hépatiques
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
CN113056270A (zh) * 2018-09-18 2021-06-29 梅塔科林公司 法尼醇x受体激动剂的结晶形式
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054634A1 (en) * 2002-05-24 2005-03-10 Brett Busch Azepinoindole derivatives as pharmaceutical agents
WO2007070796A1 (fr) * 2005-12-15 2007-06-21 Exelixis, Inc. Derives d'azepinoindole en tant qu'agents pharmaceutiques
US20080299118A1 (en) * 2007-06-01 2008-12-04 Wyeth FXR Agonists for the Treatment of Malignancies
US20090215748A1 (en) * 2007-12-20 2009-08-27 Wyeth FXR agonists for treating vitamin D associated diseases
WO2010036362A1 (fr) * 2008-09-26 2010-04-01 Wyeth Inhibiteurs des récepteurs nucléaires de 1,2,3,6-tétrahydroazépino[4,5-b]indole-5-carboxylate
WO2015138986A1 (fr) * 2014-03-13 2015-09-17 Salk Institute For Biological Studies Agonistes fxr et leurs procédés de fabrication et d'utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054634A1 (en) * 2002-05-24 2005-03-10 Brett Busch Azepinoindole derivatives as pharmaceutical agents
WO2007070796A1 (fr) * 2005-12-15 2007-06-21 Exelixis, Inc. Derives d'azepinoindole en tant qu'agents pharmaceutiques
US20080299118A1 (en) * 2007-06-01 2008-12-04 Wyeth FXR Agonists for the Treatment of Malignancies
US20090215748A1 (en) * 2007-12-20 2009-08-27 Wyeth FXR agonists for treating vitamin D associated diseases
WO2010036362A1 (fr) * 2008-09-26 2010-04-01 Wyeth Inhibiteurs des récepteurs nucléaires de 1,2,3,6-tétrahydroazépino[4,5-b]indole-5-carboxylate
WO2015138986A1 (fr) * 2014-03-13 2015-09-17 Salk Institute For Biological Studies Agonistes fxr et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FOSTER, A. B.: "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design", ADVANCES IN DRUG RESEARCH, vol. 14, 1985, pages 1 - 40, XP009086953 *

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* Cited by examiner, † Cited by third party
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US10450277B2 (en) 2014-03-13 2019-10-22 The Salk Institute For Biological Studies Analogs of fexaramine and methods of making and using
US10815203B2 (en) 2014-03-13 2020-10-27 Salk Institute For Biological Studies Analogs of fexaramine and methods of making and using
US10301268B2 (en) 2014-03-13 2019-05-28 The Salk Institute For Biological Studies Analogs of fexaramine and methods of making and using
US11440889B2 (en) 2014-03-13 2022-09-13 The Salk Institute For Biological Studies Analogs of fexaramine and methods of making and using
CN112771026A (zh) * 2018-08-30 2021-05-07 拓臻制药公司 治疗肝脏病症
WO2020042114A1 (fr) * 2018-08-30 2020-03-05 Terns Pharmaceuticals, Inc. Traitement de troubles hépatiques
CN113056270A (zh) * 2018-09-18 2021-06-29 梅塔科林公司 法尼醇x受体激动剂的结晶形式
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné

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