Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

ACS Medicinal Chemistry Letters

Volumn 7, Issue 1, 2016, Pages 51-55

  Agarwal, Sameer ^a   Patil, Amit ^a   Aware, Umesh ^a   Deshmukh, Prashant ^a   Darji, Brijesh ^a   Sasane, Santosh ^a   Sairam, Kalapatapu V V M ^a   Priyadarsiny, Priyanka ^a   Giri, Poonam ^a   Patel, Harilal ^a   Giri, Suresh ^a   Jain, Mukul ^a   Desai, Ranjit C ^a  

^a ZYDUS RESEARCH CENTRE   (India)

Author keywords

diabetes; GLP1 secretion; GPBAR1; GPR 131; TGR5; TGR5 agonist

Indexed keywords

2 [[2 [4 (1H IMIDAZOL 1 YL)PHENOXY]ETHYL]THIO] 5 [2 (3,4 DIMETHOXYPHENYL)PROPAN 2 YL] 1 (4 FLUORO PHENYL) 1H IMIDAZOLE; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; ANTIDIABETIC AGENT; G PROTEIN COUPLED RECEPTOR; GLUCOSE; IMIDAZOLE DERIVATIVE; TAKEDA G PROTEIN COUPLED RECEPTOR 5; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIDIABETIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; EC50; IN VITRO STUDY; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; PRIORITY JOURNAL; RAT;

EID: 84955454063     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.5b00323     Document Type: Article

References (30)

1. IBD Diabetes Atlas, 6 th ed.; International Diabetes Federation: Brussells, Belgium, 2013; http://www.diabetesatlas.org.
2. De Fronzo, R. A. From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus Diabetes 2009, 58, 773-795 10.2337/db09-9028
3. Nazimek-Siewniak, B.; Moczulski, D.; Grzeszczak, W. Risk of macrovascular and microvascular complications in Type 2 diabetes Results of longitudinal study design J. Diabetes Complications 2002, 16, 271-276 10.1016/S1056-8727(01)00184-2
4. Kles, K. A.; Vinik, A. I. Pathophysiology and treatment of diabetic peripheral neuropathy: The case for diabetic neurovascular functions as an essential component Curr. Diabetes Rev. 2006, 2, 131-145 10.2174/157339906776818569
5. Doyle, M. E.; Egan, J. M. Pharmacological agents that directly modulate insulin secretion Pharmacol. Rev. 2003, 55, 105-131 10.1124/pr.55.1.7
6. Ashiya, M.; Smith, R. E. T. Non-insulin therapies for type 2 diabetes Nat. Rev. Drug Discovery 2007, 6, 777-778 10.1038/nrd2420
7. Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Itadani, H.; Tanaka, K. Identification of membrane-type receptor for bile acids (M-BAR) Biochem. Biophys. Res. Commun. 2002, 298, 714-719 10.1016/S0006-291X(02)02550-0
8. Tiwari, A.; Maiti, P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders Drug Discovery Today 2009, 14, 523-530 10.1016/j.drudis.2009.02.005
9. 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 10.1016/j.bbrc.2005.01.139
10. Thomas, C.; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.; Pruzanski, M.; Pellicciari, R.; Auwerx, J.; Schoonjans, K. TGR5-mediated bile acid sensing controls glucose homeostasis Cell Metab. 2009, 10, 167-177 10.1016/j.cmet.2009.08.001
11. 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, 484-489 10.1038/nature04330
12. Gioiello, A.; Rosatelli, E.; Nuti, R.; Macchiarulo, A.; Pellicciari, R. Patented TGR5 modulators: A review (2006-present) Expert Opin. Ther. Pat. 2012, 22, 1399-1414 10.1517/13543776.2012.733000
13. Pellicciari, R.; Gioiello, A.; Macchiarulo, A.; Thomas, C.; Rosatelli, E.; Natalini, B.; Sardella, R.; Pruzanski, M.; Roda, A.; Pastorini, E.; Schoonjans, K.; Auwerx, J. Discovery of 6α-Ethyl-23(S)-methylcholic Acid (S-EMCA, INT-777) as a Potent and Selective Agonist for the TGR5 Receptor, a Novel Target for Diabesity J. Med. Chem. 2009, 52, 7958-7961 10.1021/jm901390p
14. Evans, K. A.; Budzik, B. W.; Ross, S. A.; Wisnoski, D. D.; Jin, J.; Rivero, R. A.; Vimal, M.; Szewczyk, G. R.; Jayawickreme, C.; Moncol, D. L.; Rimele, T. J.; Armour, S. L.; Weaver, S. P.; Griffin, R. J.; Tadepalli, S. M.; Jeune, M. R.; Shearer, T. W.; Chen, Z. B.; Chen, L.; Anderson, D. L.; Becherer, J. D.; De Los Frailes, M.; Colilla, F. J. Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists J. Med. Chem. 2009, 52, 7962-7965 10.1021/jm901434t
15. Herbert, M. R.; Siegel, D. L.; Staszewski, L.; Cayanan, C.; Banerjee, U.; Dhamija, S.; Anderson, J.; Fan, A.; Wang, L.; Rix, P.; Shiau, A. K.; Rao, T. S.; Noble, S. A.; Heyman, R. A.; Bischoff, E.; Guha, M.; Kabakibi, A.; Pinkerton, A. B. Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5 Bioorg. Med. Chem. Lett. 2010, 20, 5718-5721 10.1016/j.bmcl.2010.08.014
16. Budzik, B. W.; Evans, K. A.; Wisnoski, D. D.; Jin, J.; Rivero, R. A.; Szewczyk, G. R.; Jayawickreme, C.; Moncol, D. L.; Yu, H. Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists Bioorg. Med. Chem. Lett. 2010, 20, 1363-1367 10.1016/j.bmcl.2010.01.003
17. Futatsugi, K.; Bahnck, K. B.; Brenner, M. B.; Buxton, J.; Chin, J. E.; Coffey, S. B.; Dubins, J.; Flynn, D.; Gautreau, D.; Guzman-Perez, A.; Hadcock, J. R.; Hepworth, D.; Herr, M.; Hinchey, T.; Janssen, A. M.; Jennings, S. M.; Jiao, W.; Lavergne, S. Y.; Li, B.; Li, M.; Munchhof, M. J.; Orr, S. T. M.; Piotrowski, D. W.; Roush, N. S.; Sammons, M.; Stevens, B. D.; Storer, G.; Wang, J.; Warmus, J. S.; Wei, L.; Wolford, A. C. Optimization of triazole-based TGR5 agonists towards orally available agents MedChemComm 2013, 4, 205-210 10.1039/C2MD20174G
18. Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T. M.; Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S.; Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.; Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A. C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A. M.; Sharma, R.; Flynn, D. A. Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists ACS Med. Chem. Lett. 2013, 4, 63-68 10.1021/ml300277t
19. Phillips, D. P.; Gao, W.; Yang, Y.; Zhang, G.; Lerario, I. K.; Lau, T. L.; Jiang, J.; Wang, X.; Nguyen, D. G.; Bhat, B. G.; Trotter, C.; Sullivan, H.; Welzel, G.; Landry, J.; Chen, Y.; Joseph, S. B.; Li, C.; Gordon, W. P.; Richmond, W.; Johnson, K.; Bretz, A.; Bursulaya, B.; Pan, S.; McNamara, P.; Seidel, H. M. Discovery of trifluoromethyl- (pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: Structure-activity relationships, lead optimization, and chronic in vivo efficacy J. Med. Chem. 2014, 57, 3263 10.1021/jm401731q
20. Fryer, R. M.; Ng, K. J.; Nodop Mazurek, S. G.; Patnaude, L.; Skow, D. J.; Muthukumarana, A.; Gilpin, K. E.; Dinallo, R. M.; Kuzmich, D.; Lord, J.; Sanyal, S.; Yu, H.; Harcken, C.; Cerny, M. A.; Hickey, E. R.; Modis, L. K. G protein-coupled bile acid receptor 1 (GPBAR1) stimulation mediates arterial vasodilation through a KCa1.1 (BKCa)-dependent mechanism J. Pharmacol. Exp. Ther. 2014, 348, 421-431 10.1124/jpet.113.210005
21. Högenauer, K.; Arista, L.; Schmiedeberg, N.; Werner, G.; Jaksche, H.; Bouhelal, R.; Nguyen, D. G.; Bhat, B. G.; Raad, L.; Rauld, C.; Carballido, J. M. G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype J. Med. Chem. 2014, 57, 10343-10354 10.1021/jm501052c
22. Duan, H.; Ning, M.; Zou, Q.; Ye, Y.; Feng, Y.; Zhang, L.; Leng, Y.; Shen, J. Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes J. Med. Chem. 2015, 58, 3315-3328 10.1021/jm500829b
23. Macchiarulo, A.; Gioiello, A.; Thomas, C.; Massarotti, A.; Nuti, R.; Rosatelli, E.; Sabbatini, P.; Schoonjans, K.; Auwerx, J.; Pellicciari, R. 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 10.1021/ci800196h
24. Macchiarulo, A.; Gioiello, A.; Thomas, C.; Pols, T. W. H.; Nuti, R.; Ferrari, C.; Giacchè, N.; De Franco, F.; Pruzanski, M.; Auwerx, J.; Schoonjans, K.; Pellicciari, R. Probing the Binding Site of Bile Acids in TGR5 ACS Med. Chem. Lett. 2013, 4, 1158-1162 10.1021/ml400247k
25. Winterfeldt, E. Applications of diisobutylaluminium hydride (DIBAH) and triisobutylaluminium (TIBA) as reducing agents in organic synthesis Synthesis 1975, 1975, 617-630 10.1055/s-1975-34049
26. Agarwal, S.; Jain, M. R.; Patel, P. R. 2-Thio-Imidazole Derivatives as TGR5Modulators. PCT Int. Appl. WO 2013/054338, 18 April 2013, (Appl. PCT/IN2012/000471, 4.07.2012).
27. Wang, Y.-D.; Chen, W.-D.; Yu, D.; Forman, B. M.; Huang, W. 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-κB) in mice Hepatology 2011, 54, 1421-1432 10.1002/hep.24525
28. Schmidt, S.; Gonzalez, D.; Derendorf, H. Significance of protein binding in pharmacokinetics and pharmacodynamics J. Pharm. Sci. 2010, 99, 1107-1122 10.1002/jps.21916
29. Bell, R. H.; Hye, R. J. Animal models of diabetes mellitus: physiology and pathology J. Surg. Res. 1983, 35, 433-460 10.1016/0022-4804(83)90034-3
30. Shafrir, E. Animal models of non insulin dependent diabetes Diabetes/Metab. Rev. 1992, 8, 179-208 10.1002/dmr.5610080302