Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors

Bioorg Med Chem Lett. 2021 Feb 1:33:127722. doi: 10.1016/j.bmcl.2020.127722. Epub 2020 Dec 4.

Abstract

Long-chain acyl-CoA synthetase-1 (ACSL1), an enzyme that catalyzes the synthesis of long-chain acyl-CoA from the corresponding fatty acids, is believed to play essential roles in lipid metabolism. Structure activity relationship studies based on HTS hit compound 1 delivered the benzimidazole series as the first selective and highly potent ACSL1 inhibitors. Representative compound 13 exhibited not only remarkable inhibitory activity against ACSL1 (IC50 = 0.042 μM) but also excellent selectivity for the other ACSL isoforms. In addition, compound 13 demonstrated an in vivo suppression effect against the production of long-chain acyl-CoAs in mouse.

Keywords: ACSL1; Acyl-CoA; Benzimidazole; Fatty acid; SAR.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Coenzyme A Ligases / antagonists & inhibitors*
  • Coenzyme A Ligases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • benzimidazole
  • ACSL1 protein, mouse
  • Coenzyme A Ligases
  • ACSL1 protein, human