TGR5 as a therapeutic target for treating obesity

Current Topics in Medicinal Chemistry

Volumn 10, Issue 4, 2010, Pages 386-396

  Zhong, Min ^a  

^a Presidio Pharmaceuticals Inc   (United States)

Author keywords

Bile acids; G protein coupled receptor (GPCR); Metabolic syndrome; Obesity; TGR5; TGR5 modulators; Type II diabetes

Indexed keywords

5ALPHA PREGNANDIONE; ANTIOBESITY AGENT; CHENODEOXYCHOLIC ACID; CHOLIC ACID DERIVATIVE; DEOXYCHOLIC ACID; G PROTEIN COUPLED RECEPTOR; HYODEOXYCHOLIC ACID; INCRETIN; JP 200605688; JP 2006063064; LITHOCHOLIC ACID; OLEANOLIC ACID; PREGNANEDIOL; PREGNANEDIONE; TGR5 RECEPTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; URSODEOXYCHOLIC ACID; US 2004 043468; US 2006 0199795; US 2008 0221161; US 2009 0035306; US 2009 0054304; WO 2004 067008; WO 2007 110237; WO 2007 127505; WO 2008 067219; WO 2008 067222; WO 2008 070692; WO 2008 097976; WO 2008 125627; BILE ACID; GPBAR1 PROTEIN, HUMAN; LIGAND;

AMINO ACID ANALYSIS; AMINO ACID SUBSTITUTION; APOPTOSIS; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; ENERGY BALANCE; ENERGY EXPENDITURE; GLUCOSE METABOLISM; HORMONE RELEASE; HUMAN; IMMUNOMODULATION; INSULIN SENSITIVITY; LIVER PROTECTION; MACROPHAGE FUNCTION; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATENT; PHYLOGENETIC TREE; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; RECEPTOR AFFINITY; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; COMPLICATION; DRUG DELIVERY SYSTEM; DRUG EFFECTS; PROCEDURES;

BILE ACIDS AND SALTS; DRUG DELIVERY SYSTEMS; HUMANS; LIGANDS; OBESITY; RECEPTORS, G-PROTEIN-COUPLED; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77949425951     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802610790980576     Document Type: Review

References (67)

1. World Health Organization (WHO). Obesity: Preventing and Managing the Global Epidemic. Report of a WHO Consultation Geneva. WHO: Geneva, 2004.
2. Kanazawa, M.; Yoshiike, N.; Osaka, T.; Numba, Y.; Zimmet, P.; Inoue, S. Criteria and classification of obesity in Japan and Asia-Oceania. Asia Pac. J. Clin. Nutr., 2002, 11, S732-S737.
3. Zhou, B.-F. Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults: study on optimal cut-off points of body mass index and waist circumference in Chinese adults. Asia Pac. J. Clin. Nutr., 2002, 11, S685-S693.
4. (a). National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. International Medical Publishing, Inc.: McLean, VA., 1998.
5. (b). Bray, G. A. Medical consequences of obesity. J. Clin. Endocrinol. Metab., 2004, 89, 2583-2589.
6. (c). Haslam, D. W.; James, W. P. Obesity. Lancet, 2005, 366, 1197-1209.
7. (a). Allison, D. B.; Fontaine, K. R.; Manson, J. E.; Stevens, J.; VanItallie, T. B. Annual deaths attributable to obesity in the United States. J. Am. Med. Assoc., 1999, 282, 1530-1538.
8. (b). Mokdad, A. H.; Marks, J. S.; Stroup, D. F.; Gerberding, J. L. Actual causes of death in the United States, 2000. J. Am. Med. Assoc., 2004, 291, 1238-1245.
9. (c). Olshansky, S. J.; Passaro, D. J.; Hershow, R. C.; Layden, J.; Carnes, B. A.; Brody, J.; Hayflick, L.; Butler, R. N.; Allison, D. B.; Ludwig, D. S. A potential decline in life expectancy in the United States in the 21st century. New Engl. J. Med., 2005, 352, 1138-1145.
10. (d). Barness, L. A.; Opitz, J. M.; Gilbert-Barness, E. Obesity: genetic, molecular, and environmental aspects. Am. J. Med. Genet. A, 2007, 143A, 3016-3034.
11. Colditz, G. A. Economic costs of obesity and inactivity. Med. Sci. Sports Exerc., 1999, 31, S663-S667.
12. Ogden, C. L.; Carroll, M. D.; Flegal, K. M. High body mass index for age among US children and adolescents, 2003-2006. J. Am. Med. Assoc., 2008, 299, 2401-2405.
13. Finkelstein, E. A.; Fiebelkorn, I. C.; Wang, G. National medical spending attributable to overweight and obesity: how much, and who's paying? Health Aff., 2003, W3, 219-226.
14. (a). Zhang, Q.; Wang, Y. Trends in the association between obesity and socioeconomic status in U.S. adults: 1971 to 2000. Obes. Res., 2004, 12, 1622-1632.
15. (b). Wang, Y.; Zhang, Q. Are American children and adolescents of low socioeconomic status at increased risk of obesity? Changes in the association between overweight and family income between 1971 and 2002. Am. J. Clin. Nutr., 2006, 84, 707-716.
16. (c). Wang, Y.; Beydoun, M. A. The obesity epidemic in the United States - gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol. Rev., 2007, 29, 6-28.
17. Wang, Y.; Beydoun, M. A.; Liang, L.; Caballero, B.; Kumanyika, S. K. Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic. Obesity, 2008, 16, 2323-2330.
18. Zhi, J.; Melia, A. T.; Eggers, H.; Joly, R.; Patel, I. H. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J. Clin. Pharmacol., 1995, 35, 1103-1108.
19. Heal, D. J.; Aspley, S.; Prow, M. R.; Jackson, H. C.; Martin, K. F.; Cheetham, S. C. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from damphetamine and d-fenfluramine. Int. J. Obes. Relat. Metab. Disord., 1998, 22, S18-S28.
20. Reports on side-effects of Orlistat: (a). Torgerson, J. S.; Hauptman, J.; Boldrin, M. N.; Sjöström, L. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care, 2004, 27, 155-161.
21. (b). Garcia, S.; da Costa Barros, L.; Turatti, A.; Martinello, F.; Modiano, P.; Ribeiro-Silva, A.; de Oliveira Vespúcio, M.; Uyemura, S. The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen. Cancer Lett., 2006, 240, 221-224.
22. Reports on side-effects of Sibutramine: (a) Taflinski, T.; Chojnacka, J. Sibutramine-associated psychotic episode. Am. J. Psychiatry, 2000, 157, 2057-2058.
23. (b) Birkenfeld, A. L.; Schroeder, C.; Boschmann, M.; Tank, J.; Franke; G.; Luft, F. C.; Biaggioni, I.; Sharma, A. M.; Jordan, J. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation, 2002,106, 2459-2465.
24. (c) Goh, B. K.; Ng, P. P. L.; Giam, Y. C. Severe bullous drug eruption due to Sibutramine (Reductil® ). Br. J. Dermatol., 2003, 149, 215-216.
25. (d) Sayin, T.; Güldal, M. Sibutramine: possible cause of a reversible cardiomyopathy. Intl. J. Cardiol., 2005, 99, 481-482.
26. (e) Florentin, M.; Liberopoulos E. N.; Elisaf, M. S. Sibutramine- associated adverse effects: a practical guide for its safe use. Obes. Rev., 2008, 9, 378-387.
27. A number of anti-obesity drugs, including Fenfluramine, Mazindol, and Dexfenfluramine were withdrawn from the market due to severe side-effects.
28. Houten, S. M.; Watanabe, M.; Auwerx, J. Endocrine functions of bile acids. EMBO J., 2006, 25, 1419-1425.
29. Nguyen, A.; Bouscarel, B. Bile acids and signal transduction: Role in glucose homeostasis. Cell Signal., 2008, 20, 2180-2197.
30. Thomas, C.; Pellicciari, R.; Pruzanski, M.; Auwerx, J.; Schoonjans, K. Targeting bile-acid signaling for metabolic diseases. Nat. Rev. Drug Discov., 2008, 7, 678-693.
31. Keitel, V.; Kubitz, R.; Häussinger, D. Endocrine and paracrine role of bile acids. World J. Gastroenterol., 2008, 14, 5620-5629.
32. Thomas, C.; Auwerx, J.; Schoonjans, K. Bile acids and the membrane bile acid receptor TGR5-connecting nutrition and metabolism. Thyroid, 2008, 18, 167-173.
33. Kawamata, Y.; Fujii, R.; Hosoya, M.; Harada, M.; Yoshida, H.; Miwa, M.; Fukusumi, S.; Habata, Y.; Itoh, T.; Shintani, Y.; Hinuma, S.; Fujisawa, Y.; Fujino, M. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem., 2003, 278, 9435-9440.
34. Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun., 2002, 298, 714-719.
35. Yoshimura, T.; Kurita, C.; Nagao, T.; Usami, E.; Nakao, T.; Watanabe, S.; Kobayashi, J.; Yamazaki, F.; Tanaka, H.; Inagaki, N.; Nagai, H. Inhibition of tumor necrosis factor-alpha and interleukin-1-beta production by beta-adrenoceptor agonists from lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Pharmacol., 1997, 54, 144-152.
36. Vassileva, G.; Golovko, A.; Markowitz, L.; Abbondanzo, S. J.; Zeng, M.; Yang, S.; Hoos, L.; Tetzloff, G.; Levitan, D.; Murgolo, N. J.; Keane, K.; Davis, H. R. Jr.; Hedrick, J.; Gustafson, E. L. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem. J., 2006, 398, 423-430.
37. Keitel, V.; Donner, M.; Winandy, S.; Kubitz, R.; Häussinger, D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem. Biophys. Res. Commun., 2008, 372, 78-84.
38. Keitel, V.; Reinehr, R.; Gatsios, P.; Rupprecht, C.; Görg, B.; Selbach, O.; Häussinger, D.; Kubitz, R. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology, 2007, 45, 695-703.
39. 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, 386-390.
40. Watanabe, M; Houten, S. M.; Mataki, C.; Christoffolete, M. A.; Kim, B. W.; Sato, H.; Messaddeq, N.; Harney, J. W.; Ezaki, O.; Kodama, T.; Schoonjans, K.; Bianco, A. C.; Auwerx, J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 2006, 439, 484-488.
41. Maruyama, T.; Tanaka, K.; Suzuki, J.; Miyoshi, H.; Harada, N.; Nakamura, T.; Miyamoto, Y.; Kanatani A.; Tamai, Y. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J. Endocrinol., 2006, 191, 197-205.
42. Yasuda, H.; Hirata, S.; Inoue, K.; Mashima, H.; Ohnishi, H.; Yoshiba, M. Involvement of membrane-type bile acid receptor M-BAR/ 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, 154-159.
43. Yang, J. I.; Yoon, J.-H.; Myung, S. J.; Gwak, G. -Y.; Kim, W.; Chung, G. E.; Lee, S. H.; Lee, S.-M.; Kim, C. Y.; Lee, H.-S. 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, 156-161.
44. Sato, H.; Macchiarulo, A.; Thomas, C.; Gioiello, A.; Une, M.; Hofmann, A. F.; Saladin, R.; Schoonjans, K.; Pellicciari R.; Auwerx, J. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J. Med. Chem., 2008, 51, 1831-1841.
45. (a). Makishima, M.; Okamoto, A. Y.; Repa, J. J.; Tu, H.; Learned, R. M.; Luk, A.; Hull, M. V.; Lustig, K. D.; Mangelsdorf, D. J.; Shan, B. Identification of a nuclear receptor for bile acids. Science, 1999, 284, 1362-1365.
46. (b). Pellicciari, R.; Gioiello, A.; Costantino, G. Potential therapeutic applications of farnesoid X receptor (FXR) modulators. Exp. Opin.Ther. Patents, 2006, 16, 333-341.
47. (c). Kuipers, F.; Stroeve, J. H.; Caron, S.; Staels, B. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Curr. Opin. Lipidol., 2007, 18, 289-297.
48. Pellicciari, R.; Sato, H.; Gioiello, A.; Costantino, G.; Macchiarulo, A.; Sadeghpour, B. M.; Giorgi, G.; Schoonjans, K.; Auwerx, J. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6, 23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J. Med. Chem., 2007, 50, 4265-4268.
49. (a). Pellicciari, R. TGR5 modulators and methods of use thereof. Intercept Pharmaceuticals, Inc. PCT Application WO 2008/091540.
50. (b). Pellicciari, R. TGR5 modulators and methods of use thereof. Intercept Pharmaceuticals, Inc., EP Application EP 1947108, 2008.
51. Sato, H.; Genet, C.; Strehle, A.; Thomas, C.; Lobstein, A.; Wagner, A.; Mioskowski, C.; Auwerx, J.; Saladin, R. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun., 2007, 362, 793-798.
52. Schreiner, E. P.; Högenauer, K. Cholanic acid amides. Novartis Pharma Gmbh PCT Appl., WO 2008/009407.
53. (a). Herbert, M. R.; Pinkerton, A. B.; Siegel, D. L. Heterocyclic modulators of TGR5 for treatment of disease. Kalypsys, Inc., US Patent Appl. Pub., US 2009/0054304.
54. (b). Pinkerton, A. B.; Kabakibi, A.; Hoffman, T. Z.; Siegel, D. L.; Noble, S. A. Quinazolinone modulators of TGR5. Kalypsys, Inc., US Patent Appl. Pub., US 2009/0035306.
55. (c). Pinkerton, A. B.; Kabakibi, A.; Hoffman, T. Z.; Siegel, D. L.; Noble, S. A. Quinazolinone modulators of TGR5. Kalypsys, Inc., PCT Appl., WO 2008/067219.
56. (d). Pinkerton, A. B.; Kabakibi, A.; Herbert, M. R.; Siegel, D. Heterocyclic modulators of TGR5 for treatment of disease. Kalypsys, Inc., US Patent Appl. Pub., US 2008/0221161.
57. (e). Pinkerton, A. B.; Kabakibi, A.; Herbert, M. R.; Siegel, D. L. Heterocyclic modulators of TGR5 for treatment of disease. Kalypsys, Inc., PCT Appl., WO 2008/097976.
58. (f). Pinkerton, A. B.; Kabakibi, A.; Gahman, T. C. Heterocyclic modulators of TGR5. Kalypsys, Inc., PCT Appl., WO 2008/067222.
59. (a). Arista, L. Pyridazine-, pyridine- and pyrane- derivatives as GPBAR1 agonists. Novartis AG. PCT Appl., WO 2008/125627.
60. (b). Arista, L.; Högenauer, K.; Schmiedeberg, N.; Werner, G.; Jaksche, H. Heterocyclic amides for use as pharmaceuticals. Novartis Pharma Gmbh. PCT Appl., WO 2007/110237.
61. (a). Fang, J.; Tang, J.; Carpenter, A. J.; Peckham, G.; Conlee, C. R.; Du, K. S.; Katamreddy, S. R. Chemical compounds and uses. Smithkline Beecham. PCT Appl., WO 2008/070692.
62. (b). Szewczyk, J. R.; Laudeman, C. P.; Evans, K. A.; Li, Y. H.; Dock, S. T.; Chen, Z. Chemical compounds. Smithkline Beecham Co. PCT Appl., WO 2007/127505.
63. (a) Itoh, F.; Hard, N.; Kobayashi, H.; Kanzaki, N. Preparation of N-heterocyclic compounds as G protein-coupled receptor (TGR5) agonists. Takeda Chemical Industrials, Ltd. Jpn. Kokai Tokkyo Koho JP, 2006063064.
64. (b) Itoh, F.; Tawaraishi, T.; Hirohashi, M.; Matsumoto, H. Preparation of fused pyridine compounds as TGR5 receptor agonists. Takeda Chemical Industrials, Ltd. Jpn. Kokai Tokkyo Koho JP, 2006056881.
65. (c) Itoh, F.; Hinuma, S.; Kanzaki, N.; Miki, T.; Kawamata, Y.; Oi, S.; Tawaraishi, T.; Ishichi, Y,; Hirohashi, M. Receptor agonists. Takeda Pharmaceuticals North America, Inc. US Patent Appl. Pub., US 2006/0199795.
66. (d) Itoh, F.; Hinuma, S.; Kanzaki, N.; Miki, T.; Kawamata, Y.; Oi, S.; Tawaraishi, T.; Ishichi, Y.; Hirohashi, M. Receptor agonists. Takeda Chemical Industrials, Ltd., WO 2004/067008.
67. (e) Hinuma, S.; Fuji, R.; Kawamata, Y.; Komatsu, H.; Uejima, H.; Itoh, F. Screening method. Takeda Chemical Industrials, Ltd., WO 2004/043468.