Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives

Bioorg Med Chem. 2010 Apr 1;18(7):2785-95. doi: 10.1016/j.bmc.2010.01.067. Epub 2010 Feb 4.

Abstract

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.

MeSH terms

  • Animals
  • Baculoviridae / genetics
  • Cell Line
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Ethylenediamines / chemical synthesis*
  • Ethylenediamines / pharmacokinetics
  • Ethylenediamines / pharmacology*
  • Humans
  • In Vitro Techniques
  • Indicators and Reagents
  • Insecta
  • Mice
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Microsomes, Liver / metabolism
  • Myoblasts / drug effects
  • Myoblasts / enzymology
  • Oxidation-Reduction
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Ethylenediamines
  • Indicators and Reagents
  • Dgat1 protein, rat
  • Diacylglycerol O-Acyltransferase