Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC)

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1380-1385. doi: 10.1016/j.bmcl.2019.03.039. Epub 2019 Mar 27.

Abstract

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Keywords: A(2A) receptor; ACAT1; Benzimidazole; Cyclohexane acetic acid; DGAT1 inhibitor; High throughput purification; Lipid tolerance test; Parallel medicinal chemistry; Pharmacokinetics; Triglyceride.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Chemistry, Pharmaceutical
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Diacylglycerol O-Acyltransferase / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • DGAT1 protein, human
  • Diacylglycerol O-Acyltransferase