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Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders.
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.
Affiliation
  • Moore F; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Wang W; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Zhao G; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Mignone J; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Meng W; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Chu CH; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Ma Z; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Azzara A; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Cullen MJ; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Pelleymounter MA; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Appiah K; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Cvijic ME; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Dierks E; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Chang S; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Foster K; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Kopcho L; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • O'Malley K; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Li YX; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Khandelwal P; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Whaley JM; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Mathur A; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Hou X; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Wu DR; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Robl JA; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Cheng D; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States.
  • Devasthale P; Bristol Myers Squibb Research & Development, P.O. Box 4000, Princeton, NJ, 08543, United States. Electronic address: pratik.devasthale@bms.com.
Bioorg Med Chem Lett ; 91: 129362, 2023 07 15.
Article in En | MEDLINE | ID: mdl-37295614
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Monoglycerides / Metabolic Diseases Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2023 Document type: Article Affiliation country: Estados Unidos
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Monoglycerides / Metabolic Diseases Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2023 Document type: Article Affiliation country: Estados Unidos