Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

ACS Medicinal Chemistry Letters

Volumn 6, Issue 8, 2015, Pages 936-941

  Liu, Ping ^a   Hu, Zhiyong ^a   Dubois, Byron G ^a   Moyes, Christopher R ^a   Hunter, David N ^a   Zhu, Cheng ^a   Kar, Nam Fung ^a   Zhu, Yuping ^a   Garfunkle, Joie ^a   Kang, Ling ^a   Chicchi, Gary ^a   Ehrhardt, Anka ^a   Woods, Andrea ^a   Seo, Toru ^a   Woods, Morgan ^a   Van Heek, Margaret ^a   Dingley, Karen H ^a   Pang, Jianmei ^a   Salituro, Gino M ^a   Powell, Joyce ^a   Terebetski, Jenna L ^a   Hornak, Viktor ^a   Campeau, Louis Charles ^a   Lamberson, Joe ^a   Ujjainwalla, Fez ^a   Miller, Michael ^a   Stamford, Andrew ^a   Wood, Harold B ^a   Kowalski, Timothy ^a   Nargund, Ravi P ^a   Edmondson, Scott D ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Benzyloxy analogues; Chiral cis cyclopropanes; GPR119 agonists; oGTT; Type II diabetes

Indexed keywords

ANTIDIABETIC AGENT; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 119 AGONIST; GLUCOSE; MBX 2982; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CRYSTALLIZATION; CYCLIZATION; DOG; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SOLUBILITY; DRUG SYNTHESIS; EC50; ELIMINATION HALF-LIFE; GLUCOSE BLOOD LEVEL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; MEAN RESIDENCE TIME; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; PH; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RAT; RHESUS MONKEY; SPECIES DIFFERENCE; STRUCTURE ACTIVITY RELATION; VOLUME OF DISTRIBUTION;

EID: 84938932537     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.5b00207     Document Type: Article

References (35)

1. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care 2009, 32, 1327-1334. 10.2337/dc09-9033
2. Skyler, J. S. Pathogenesis of type 2 diabetes mellitus J. Med. Chem. 2004, 47, 4113-4117 10.1021/jm0306273
3. Goldberg, R. B.; Holman, R.; Drucker, D. J. Management of type 2 diabetes N. Engl. J. Med. 2008, 358, 293-297 10.1056/NEJMclde0708469
4. Soga, T.; Ohishi, T.; Matsui, T.; Saito, T.; Matsumoto, M.; Takasaki, J.; Matsumoto, S.; Kamohara, M.; Hiyama, H.; Yoshida, S.; Momose, K.; Ueda, Y.; Matsushime, H.; Kobori, M.; Furuichi, K. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G protein-coupled receptor Biochem. Biophys. Res. Commun. 2005, 326, 744-751 10.1016/j.bbrc.2004.11.120
5. Chu, Z.; Carroll, C.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Pedraza, M.; Mondala, H.; Gao, H.; Bagnol, D.; Chen, R.; Jones, R. M.; Behan, D. P.; Leonard, J. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release Endocrinology 2008, 149, 2038-2047 10.1210/en.2007-0966
6. Sakamoto, Y.; Inoue, H.; Kawakami, S.; Miyawaki, K.; Miyamoto, T.; Mizuta, K.; Itakura, M. Expression and distribution of Gpr119 in the pancreatic islets of mice and rats: Predominant localization in pancreatic polypeptide-secreting PP-cells Biochem. Biophys. Res. Commun. 2006, 351, 474-480 10.1016/j.bbrc.2006.10.076
7. Gao, J.; Tian, L.; Weng, G.; Bhagroo, N. V.; Sorenson, R. L.; O'Brien, T. D.; Luo, J.; Guo, Z. Stimulating beta Cell Replication and Improving Islet Graft Function by GPR119 Agonists Transplant Int. 2011, 24, 1124-1134 10.1111/j.1432-2277.2011.01332.x
8. Ohishi, T.; Yoshida, S. The Therapeutic Potential of GPR119. Agonists for Type 2 Diabetes Expert Opin. Invest. Drugs 2012, 21, 321-328 10.1517/13543784.2012.657797
9. Dhayal, S.; Morgan, N. G. The Significance of GPR119 Agonists as a Future Treatment for Type 2 Diabetes Drug News Perspect. 2010, 23, 418-424 10.1358/dnp.2010.23.7.1468395
10. Polli, J. W.; Hussey, E.; Bush, M.; Generaux, G.; Smith, G.; Collins, D.; McMullen, S.; Turner, N.; Nunez, D. J. Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design Xenobiotica 2013, 43, 498-508 10.3109/00498254.2012.739719
11. Katz, L. B.; Gambale, J. J.; Rothenberg, P. L.; Vanapalli, S. R.; Vaccaro, N.; Xi, L.; Sarich, T. C.; Stein, P. P. Effects of JNJ-38431055, a Novel GPR119 Receptor Agonist, in Randomized, Double-Blind, Placebo-Controlled Studies in Subjects with Type 2 Diabetes Diabetes, Obes. Metab. 2012, 14, 709-716 10.1111/j.1463-1326.2012.01587.x
12. Shah, U. GPR119 agonists: A promising new approach for the treatment of type 2 diabetes and related metabolic disorders Curr. Opin. Drug Discovery Dev. 2009, 12, 519-532
13. Wood, H. B.; Szewczyk, J. W.; Huang, Y.; Adams, A. D. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment. WO 2009129036 A1, 2009.
14. Szewczyk, J. W.; Acton, J.; Adams, A. D.; Chicchi, G.; Freeman, S.; Howard, A. D.; Huang, Y.; Li, C.; Mosely, R.; Murphy, E.; Samuel, R.; Santini, C.; Yang, M.; Zhang, Y.; Zhao, K.; Wood, H. B. Design of potent and selective GPR119 agonists for type II diabetes Bioorg. Med. Chem. Lett. 2011, 21, 2665-2669 10.1016/j.bmcl.2010.12.086
15. For the composition of the FaSSIF, see Table 13 in Dressman, J. B.; Amidon, G. L.; Reppas, C.; Shah, V. P. Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms Pharm. Res. 1998, 15, 11-22 10.1023/A:1011984216775
16. For an introduction to biorelevant media, such as fasted state simulated intestinal fluid (FaSSIF), see: Galia, E.; Nicolaides, E.; Horter, D.; Lobenberg, R.; Reppas, C.; Dressman, J. B. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs Pharm. Res. 1998, 15, 698-705 10.1023/A:1011910801212
17. FaSSIF solubility was used as one of the key parameters during the optimization of this lead series since it was demonstrated that dissolution testing in biorelevant media such as FaSSIF mimics the in vivo situation more closely, which provides better in vitro / in vivo correlation; see: Dressman, J. B.; Reppas, C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs Eur. J. Pharm. Sci. 2000, 11 (Suppl. 2) S73-S80 10.1016/S0928-0987(00)00181-0
18. Oh, D. M.; Curl, R.; Amidon, G. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model Pharm. Res. 1993, 10, 264-270 10.1023/A:1018947113238
19. Martinez, M.; Amidon, G. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals J. Clin. Pharmacol. 2002, 42, 620-643 10.1177/00970002042006005
20. Rohrs, B. R. Biopharmaceutics Modeling and the Role of Dose and Formulation on Oral Exposure. In Optimizing the "Drug-Like" Properties of Leads in Drug Discovery; Borchardt, R. T.; Hageman, M. J.; Stevens, J. L.; Kerns, E. H.; Thakker, D. R., Eds; Springer: New York, 2006; Vol. IV, pp 151-166.
21. Wuelfing, W. P.; Daublain, P.; Kesisoglou, F.; Templeton, A.; McGregor, C. Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species Mol. Pharmaceutics 2015, 12, 1031-1039 10.1021/mp500504q
22. Desai, D.; Wang, J.; Wen, H.; Li, X.; Timmins, P. Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms Pharm. Dev. Technol. 2013, 18, 1265-1276 10.3109/10837450.2012.660699
23. Benet, L. Z.; Zia-Amirhosseini, P. Basic Principles of Pharmacokinetics Toxicol. Pathol. 1995, 23, 115-123 10.1177/019262339502300203
24. Smith, D. A.; Beaumont, K.; Maurer, T. S.; Di, L. Volume of Distribution in Drug Design J. Med. Chem. 2015, 10.1021/acs.jmedchem.5b00201
25. Hopkins, A. L.; Keserü, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nat. Rev. Drug Discovery 2014, 13, 105-121 10.1038/nrd4163
26. Corey, E. J.; Fuchs, P. L. A synthetic method for formyl to ethynyl conversion Tetrahedron Lett. 1972, 13, 3769-3772 10.1016/S0040-4039(01)94157-7
27. Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. Enantioselective Cyclopropanation of Allylic Alcohols with Dioxaborolane Ligands: Scope and Synthetic Applications J. Am. Chem. Soc. 1998, 120, 11943-11952 10.1021/ja982055v
28. Zhu, H. Y.; Cooper, A. B.; Desai, J. A.; Wang, J.-S.; Rane, D. F.; Doll, R. J.; Njoroge, F. G.; Girijavallabhan, V. M. Novel farnesyl protein transferase inhibitors as antitumor agents. WO 2005014577 A1, 2005.
29. Jones, R. M.; Semple, G.; Xiong, Y.; Shin, Y.-J.; Ren, A. S.; Calderon, I.; Choi, J. S. K.; Fioravanti, B.; Lehmann, J.; Bruce, M. A. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto. WO 2005007647 A1, 2005.
30. Sham, H. L.; Konradi, A. W.; Hom, R. K.; Probst, G. D.; Bowers, S.; Truong, A.; Neitz, R. J.; Sealy, J.; Toth, G. Preparation of N -(thiophen-3-yl)acetamide derivatives as inhibitors of JNK N-terminal kinase. WO 2010091310 A1, 2010.
31. Measured by PatchXpress systems. For a review on ion channels, see: Aidley, D. J.; Stanfield, P. R., Eds. Ion Channels: Molecules in Action; Cambridge University Press: Cambridge, U.K., 1996.
32. Pregnane X receptor (PXR) is a nuclear receptor known to regulate expression of drug-metabolizing enzymes including cytochrome P450 (CYP450), see: Chu, V. In vitro and in vivo induction of cytochrome P450: A survey of the current practices and recommendations: A Pharmaceutical Research and Manufacturers of America perspective Drug Metab. Dispos. 2009, 37, 1339-1354 10.1124/dmd.109.027029
33. Andrikopoulos, S.; Blair, A. R.; Deluca, N.; Fam, B. C.; Proietto, J. Evaluating the glucose tolerance test in mice Am. J. Physiol. Endocrinol. Metab. 2008, 295, E1323-1332 10.1152/ajpendo.90617.2008
34. Roberts, B.; Gregoire, F. M.; Karpf, D. B.; Clemens, E.; Lavan, B.; Johnson, F.; Mcwherter, C. A.; Martin, R.; Wilson, M. MBX-2982, a Novel Oral GPR119 Agonist for the Treatment of Type 2 Diabetes: Results of Single & Multiple Dose Studies, American Diabetes Association, 69th Meetings, New Orleans, 2009.
35. Leeson, P. D.; Young, R. J. Molecular Property Design: Does Everyone Get It? ACS Med. Chem. Lett. 2015, 6, 722-725 10.1021/acsmedchemlett.5b00157