Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders
| Autor: | Shu Chang, Anthony V. Azzara, Yi-Xin Li, Marta Dabros, James Kempson, Reshma Panemangelor, Huji Turdi, Kimberly A. Foster, William J. Keim, Jean M. Whaley, Jeffrey A. Robl, Fang Moore, Luping Chen, Mary Jane Cullen, Xiaoping Hou, Atsu Apedo, R. Michael Lawrence, Arvind Mathur, David G. Harden, Wei Meng, Kevin O'Malley, Mary Ann Pelleymounter, Hannguang Chao, Pratik Devasthale, Jon J. Hangeland, Zhengping Ma, Dauh-Rurng Wu, Robert Paul Brigance, Guohua Zhao, Lynn M. Abell, Qi Gao, Susan Harvey, Lisa M. Kopcho, Dong Cheng, Elizabeth A. Dierks, Ching-Hsuen Chu, Suzanne Rooney, Xiang-Yang Ye, Saleem Ahmad, Wei Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Metabolism
Metabolic stability Pharmacology Crystallography X-Ray N-Acetylglucosaminyltransferases High-Throughput Screening Assays Structure-Activity Relationship chemistry.chemical_compound Metabolic Diseases chemistry Pharmacokinetics Tolerability In vivo Drug Discovery Animals Humans Molecular Medicine Potency Tetrazole Enzyme Inhibitors IC50 |
| Zdroj: | Journal of Medicinal Chemistry. 64:14773-14792 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species. |
| Databáze: | OpenAIRE |
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