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. 2023 Jul 15:91:129362.
doi: 10.1016/j.bmcl.2023.129362. Epub 2023 Jun 8.

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

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

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

Fang Moore et al. Bioorg Med Chem Lett. .

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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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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