Patented TGR5 modulators: A review (2006 - Present)

Expert Opinion on Therapeutic Patents

Volumn 22, Issue 12, 2012, Pages 1399-1414

  Gioiello, Antimo ^a   Rosatelli, Emiliano ^a   Nuti, Roberto ^a,b   MacChiarulo, Antonio ^a   Pellicciari, Roberto ^a,b  

^a UNIVERSITY OF PERUGIA   (Italy)

^b TES Pharma Srl   (Italy)

Author keywords

Atherosclerosis; Bile acid; Diabesity; G protein coupled receptor; Glucagon like peptide 1; Liver disease; Metabolic syndrome; Structure activity relationships; TGR5

Indexed keywords

3 ARYL 4 ISOXAZOLECARBOXAMIDE DERIVATIVE; 6 METHYL 2 OXO 4 THIOPHEN 2 YL 1,2,3,4 TETRAHYDROPYRIMIDINE 5 CARBOXYLIC ACID BENZYL ESTER; 6ALPHA ETHYLMETHYLCHENODEOXYCHOLIC ACID; 6ALPHA ETHYLMETHYLCHOLIC ACID; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; AMIDE; BETULIC ACID; CARBOXYLIC ACID DERIVATIVE; CHENODEOXYCHOLIC ACID DERIVATIVE; CHOLIC ACID DERIVATIVE; DIAZEPINE DERIVATIVE; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR TGR5; G PROTEIN COUPLED RECEPTOR TGR5 MODULATOR; HETEROCYCLIC COMPOUND; IMIDAZOLE DERIVATIVE; INT 777; ISOQUINOLINE DERIVATIVE; OBETICHOLIC ACID; OLEANOLIC ACID DERIVATIVE; OXAZEPINE DERIVATIVE; PTERIDINE DERIVATIVE; PYRAZOLE DERIVATIVE; RUP 43; SB 756050; SB 756060; THIAZOLE DERIVATIVE; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; URSOLIC ACID; XL 475;

ANTIINFLAMMATORY ACTIVITY; ATHEROSCLEROSIS; DIABETES MELLITUS; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG METABOLISM; DRUG POTENCY; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; ENERGY EXPENDITURE; FATTY LIVER; GENE DELETION; GLYCEMIC CONTROL; HUMAN; INSULIN RESISTANCE; LIVER DISEASE; LIVER FUNCTION; METABOLIC SYNDROME X; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATENT; PHYSICAL CHEMISTRY; PRIMARY BILIARY CIRRHOSIS; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION;

ANIMALS; ATHEROSCLEROSIS; BLOOD GLUCOSE; CARDIOVASCULAR AGENTS; DIABETES MELLITUS; DRUG DESIGN; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN RESISTANCE; LIGANDS; MOLECULAR STRUCTURE; PATENTS AS TOPIC; PROTEIN CONFORMATION; RECEPTORS, G-PROTEIN-COUPLED; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84869755410     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2012.733000     Document Type: Review

References (94)

1. Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res 2012;53:1723-37
2. Pols TWH, Noriega LG, Nomura M, et al. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011;54:1263-72
3. Tiwari A, Maiti P. TGR5: An emerging bile acid G-protein coupled receptor target for the potential treatment of metabolic disorders. Drug Discov Today 2009;14:523-30
4. Keitel V, Haussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenetrol 2012;published online 18 April 2012; doi:10.1016/j. clinre.2012.03.008
5. Chen X, Lou G, Meng Z, et al. TGR5: A novel target for weight maintenance and glucose metabolism. Exp Diab Res 2011;Article ID 853501:5 pagesdoi: 10.1155/2011/853501
6. Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002;298:714-19
7. Kawamata Y, Fujii R, Hosoya M, et al. A G-protein coupled receptor responsive to bile acids. J Biol Chem 2003;78:9435-40
8. Keitel V, Cupisti K, Ullmer C, et al. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009;50:861-70
9. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484-9
10. Poole DP, Godfrey C, Cattaruzza F, et al. Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 2010;22:814-26
11. Keitel V, Reinehr R, Gatsios P, et al. The G protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007;45:695-704
12. Keitel V, Donner M, Winandy S, et al. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84
13. Thomas C, Pellicciari R, Pruzanski M, et al. Targeting bile acid signalling for metabolic diseases. Nat Rev Drug Discov 2008;7:1-17
14. Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun 2005;329:386-90
15. Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167-77
16. Vassileva G, Hu W, Hoos L, et al. Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice. J Endocrinol 2010;205:225-32
17. Lavoie B, Balemba OB, Godfrey C, et al. Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol 2010;588:3295-305
18. Li T, Holmstrom SR, Kir S, et al. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 2011;25:1066-71
19. Wang YD, Chen WD, Yu D, et al. The G-Protein-coupled bile acid receptor, gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-jB) in mice. Hepatology 2011;54:1421-32
20. Xu Y. Bile acid receptor modulators in metabolic disease. Ann Rep Med Chem 2011;46:69-87
21. Sato H, Macchiarulo A, Gioiello A, et al. Novel potent and selective bile acid derivatives as TGR5 agonists: Biological screening, structure-activity relationship, and molecular modelling studies. J Med Chem 2008;51:1831-41
22. Staudinger JL, Goodwin B, Jones JA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. PNAS 2001;98:3369-74
23. Makishima M, Lu TT, Xie W, et al. Vitamin D receptor as an intestinal bile acid sensor. Science 2002;269:1313-16
24. Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science 1999;284:1362-5
25. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: Natural ligands for an orphan nuclear receptor. Science 1999;284:1365-8
26. Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999;3:543-53
27. Katona BW, Cummins CL, Ferguson AD, et al. Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids. J Med Chem 2007;50:6048-58
28. Pellicciari R, Sato H, Gioiello A, et al. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkylsubstituted bile acid derivative as selective modulators for the G-protein coupled receptor TGR5. J Med Chem 2007;50:4265-8
29. Macchiarulo A, Gioiello A, Thomas C, et al. Molecular field analysis and 3D-quantitative structure-activity relationship study (MFA 3D-QSAR) unveil novel features of bile acid recognition at TGR5. J Chem Inf Model 2008;48:1792-801
30. Pellicciari R, Gioiello A, Macchiarulo A, et al. Discovery of 6alpha-ethyl-23(S)-methyl cholic acid (S-EMCA, INT777) as potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem 2009;52:7958-61
31. Pellicciari R, Gioiello A, Sabbatini P, et al. Avicholic acid: A lead compound from birds on the route to potent TGR5 modulators. ACS Med Chem Lett 2012;3:273-7
32. Iguchi Y, Nishimaki-Mogami T, Yamaguchi M, et al. Effects of chemical modification of ursodeoxycholic acid on TGR5 activation. Biol Pharm Bull 2011;34:1-7
33. Intercept Pharmaceuticals. TGR5 modulators and methods for use thereof. WO091540A2; 2008
34. Intercept Pharmaceuticals. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions. WO002573A2; 2008
35. Intercept Pharmaceuticals. TGR5 modulators and methods for use thereof. WO059859A1; 2010
36. Intercept Pharmaceuticals. TGR5 modulators and methods for use thereof. US0172198A1; 2011
37. Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl- chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002;45:3569-72
38. Pols TWH, Nomura M, Harach T, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011;14:747-57
39. Rizzo G, Passeri D, De Franco F, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol 2010;78:617-30
40. Baghdasaryan A, Claudel T, Gumhold J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO3- output. Hepatology 2011;54:1303-13
41. Novartis pharma GMBH. Cholanic acid amides. WO009407A2; 2008
42. Sato S, Genet C, Strehle A, et al. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem Biophys Res Commun 2007;362:793-8
43. Wenming L, Chiwai W. Oleanolic acid is a selective Farnesoid X receptor modulator. Phytother Res 2010;24:369-73
44. Genet C, Strehle A, Schmidt C, et al. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist and its synthetic derivatives: Potential impact in diabetes. J Med Chem 2010;53:178-90
45. Genet C, Schmidt C, Strehle A, et al. Redefining the TGR5 triterpenoid binding pocket at the C-3 position. ChemMedChem 2010;5:1893-0
46. Merck patent GMBH. New terpenes and macrocycles. WO146772; 2009
47. Takeda Pharmaceuticals. WO043468A1; 2004
48. Takeda Pharmaceuticals. Receptor agonists. EP1591120A1; 2004
49. Takeda Pharmaceuticals. Receptor agonists. US7625887B2; 2009
50. Takeda Pharmaceuticals. Therapeutic agent for irritable bowel syndrome. WO01655A2; 2010
51. Takeda Pharmaceuticals. Therapeutic agent for irritable bowel syndrome. US136778; 2011
52. Takeda Pharmaceuticals. Therapeutic agent for irritable bowel syndrome. EP2322222; 2011
53. Kelly SJ. Missing link identified: GpBAR1 is a neuronal bile acid receptor. Neurogastroenterol Motil 2010;22:711-17
54. Arena Pharmaceuticals. Human G protein-coupled receptor and modulators thereof for treatment of hyperglycemia and related disorders. WO116653; 2005
55. SmithKline Beecham Corp. Chemical compounds. WO127505; 2007
56. Evans K, Budzik B, Ross SA, et al. Discovery of 3-aryl-4- isoxazolecarboxamides as TGR5 receptor agonists. J Med Chem 2009;52:7962-5
57. Budzik B, Evans KA, Wisnoski DD, et al. Synthesis and structure-activity relationship of a series 3-aryl-4-isoxazolcarboxamides as new class of TGR5 agonists. Bioorg Med Chem Lett 2010;20:1363-7
58. Novartis pharma GMBH. Heterocyclic amides for use as pharmaceuticals. WO110237A2; 2007
59. Novartis pharma GMBH. Pyridazine, pyridine and pyrane-derivatives as GPBAR1 agonists. WO125627A1; 2008
60. Kalypsys. Heterocyclic modulators of TGR5. WO067222A1; 2008
61. Kalypsys. Quinazoline modulators of TGR5. WO067219A2; 2008
62. Kalypsys. Heterocyclic modulators of TGR5 for treatment of disease. WO221161A1; 2008
63. Kalypsys. Heterocyclic modulators of TGR5. WO014739A2; 2010
64. Kalypsys. Heterocyclic modulators of TGR5 for treatment of disease. WO016846A1; 2010
65. Kalypsys. Heterocyclic modulators of TGR5 for treatment of disease. WO097976A1; 2008
66. Herbert MR, Siegel DL, Staszewski L, et al. Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonist of the bile acid receptor TGR5. Bioorg Med Chem Lett 2010;20:5718-21
67. Exelixis. Triazole and imidazole derivatives for use as TGR5 agonists in the treatment of diabetes and obesity. WO0938845; 2010
68. Exelixis. TGR5 agonists. WO071565A1; 2011
69. Banyu Pharmaceuticals. Novel isoquinoline derivatives. WO117084A1; 2010
70. Banyu Pharmaceuticals. Novel isoquinolinyloxymethyl heteroaryl derivatives. WO117090A1; 2010
71. Hoffmann-La Roche. Novel phenyl amide or pyridyl amide derivatives and their use as GPBAR1 agonists. WO049302A1; 2010
72. Hoffman-La Roche. 4-phenoxy-nicotinamide or 4-phenoxypyrimidine-5- carboxamide compounds. WO089099A1; 2011
73. IRM LLC. Compounds and compositions as TGR5 agonists. WO082947A1; 2012
74. Baffy GJ. Kuper cells in non-alcoholic fatty liver disease: The emerging view. J Hepatol 2009;51:212-23
75. Baker RG, Hayden MS, Ghosh S. NFkappaB, inflammation, and metabolic disease. Cell Metab 2011;13:11-22
76. Vassileva G, Golovko A, Markowitz L, et al. Targeted deletion of Gpbr1 protects mice from cholesterol gallstone formation. Biochem J 2006;398:423-30
77. Hols JJ. The Physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-39
78. Knop FK, Vilsbøll T, Holst JJ. Incretin-based therapy of type 2 diabetes mellitus. Curr Protein Pept Sci 2009;10:46-55
79. Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: A newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res 2006;3:159-65
80. Nauck MA, Meier JJ. Pharmacotherapy: GLP-1 analogues and insulin: Sound the wedding bells? Nat Rev Endocrinol 2011;7:193-5
81. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: Systematic review and meta-analysis. Am J Med 2009;122:248-56
82. Robinson MK. Surgical treatment of obesity - weighing the facts. N Engl J Med 2009;361:520-1
83. Patty ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: Potential contribution to improved glucose and lipid metabolism. Obesity 2009;17:1671-7
84. Nakatania H, Kasamab H, Oshirob T, et al. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism 2009;58:1400-7
85. Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009;6:399-409
86. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997;46:3-26
87. Yang JI, Yoon JH, Myung SJ, et al. Bile acid-induced TGR5 dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem Biophys Res Commun 2007;361:156-61
88. Yasuda H, Hirata S, Inoue K, et al. Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophys Res Commun 2007;354:154-9
89. Keitel V, Gorg B, Bidmon HJ, et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010;58:1794-805
90. Desai MS, Shabier Z, Taylor M, et al. Hypertrophic cardiomyopathy and dysregulation of cardiac energetics in a mouse model of biliary fibrosis. Hepatology 2010;51:2097-107
91. First-time-in-humans study to assess safety, pharmacokinetics & pharmacodynamics of SB756050. Available from: Http://clinicaltrials.gov/ct2/ show/NCT00607906?term=SB-756050&rank=1 [Last accessed 10 September 2012]
92. A study to test how SB756060 affects subjects with type 2 diabetes mellitus after 6 days of dosing. Available from: Http://clinicaltrials.gov/ct2/ show/NCT 00733577?term=SB-756050&rank=2 [Last accessed 10 September 2012]
93. Exelixis XL475. Available from: Http://www.exelixis.com/pipeline/xl475 [Last accessed 10 September 2012]
94. Harac T, Pols TWH, Nomura M, et al. TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci Rep 2012;2:1-7