Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors

Bioorg Med Chem Lett. 2016 Jan 1;26(1):25-32. doi: 10.1016/j.bmcl.2015.11.046. Epub 2015 Nov 25.

Abstract

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Keywords: DGAT-1 inhibitors; Diacylglycerol acyltransferase type 1; Metabolic lability; Oxadiazole; Solubility; Thiadiazole.

MeSH terms

  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Diacylglycerol O-Acyltransferase / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*

Substances

  • Enzyme Inhibitors
  • Oxadiazoles
  • Thiadiazoles
  • DGAT1 protein, human
  • Diacylglycerol O-Acyltransferase