Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2498-2503. doi: 10.1016/j.bmcl.2018.05.055. Epub 2018 Jun 4.

Abstract

Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice.

Keywords: ACC2 inhibitor; Benzothiazole; Olefin; Type 2 diabetes.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / metabolism
  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Alkenes
  • Enzyme Inhibitors
  • ACACB protein, human
  • Acacb protein, mouse
  • Acetyl-CoA Carboxylase