2. Academic Validation
  3. Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders

Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders

  • Bioorg Med Chem Lett. 2023 Jul 15;91:129362. doi: 10.1016/j.bmcl.2023.129362.
Fang Moore 1,  Wei Wang 1,  Guohua Zhao 1,  James Mignone 1,  Wei Meng 1,  Ching-Hsuen Chu 1,  Zhengping Ma 1,  Anthony Azzara 1,  Mary Jane Cullen 1,  Mary Ann Pelleymounter 1,  Kingsley Appiah 1,  Mary Ellen Cvijic 1,  Elizabeth Dierks 1,  Shu Chang 1,  Kimberly Foster 1,  Lisa Kopcho 1,  Kevin O'Malley 1,  Yi-Xin Li 1,  Purnima Khandelwal 1,  Jean M Whaley 1,  Arvind Mathur 1,  Xiaoping Hou 1,  Dauh-Rurng Wu 1,  Jeffrey A Robl 1,  Dong Cheng 1,  Pratik Devasthale 2
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • 2 Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States. Electronic address: [email protected].
PMID: 37295614 DOI: 10.1016/j.bmcl.2023.129362
Abstract

Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.

Keywords

Glucuronidation; MGAT2; Metabolic diseases; NASH; Obesity; Pyridinones; Tautomerism; Tetrazoles; Weight loss.

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