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. Epub 2023 Jun 8.

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.

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Metabolic Diseases* / drug therapy
  • Monoglycerides*
  • Obesity / drug therapy

Substances

  • Monoglycerides
  • Enzyme Inhibitors