Bioorganic & medicinal chemistry letters · 2023
Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders.
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Moore Fang, Wang Wei, Zhao Guohua, Mignone James, Meng Wei, Chu Ching-Hsuen, Ma Zhengping, Azzara Anthony, Cullen Mary Jane, Pelleymounter Mary Ann, Appiah Kingsley, Cvijic Mary Ellen, Dierks Elizabeth, Chang Shu, Foster Kimberly, Kopcho Lisa, O'Malley Kevin, Li Yi-Xin, Khandelwal Purnima, Whaley Jean M, Mathur Arvind, Hou Xiaoping, Wu Dauh-Rurng, Robl Jeffrey A, Cheng Dong, Devasthale Pratik
Аннотация
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.