Design and synthesis of small molecule glycerol 3-phosphate acyltransferase inhibitors

J Med Chem. 2009 May 28;52(10):3317-27. doi: 10.1021/jm900251a.


The incidence of obesity and other diseases associated with an increased triacylglycerol mass is growing rapidly, particularly in the United States. Glycerol 3-phosphate acyltransferase (GPAT) catalyzes the rate-limiting step of glycerolipid biosynthesis, the acylation of glycerol 3-phosphate with saturated long-chain acyl-CoAs. In an effort to produce small molecule inhibitors of this enzyme, a series of benzoic and phosphonic acids was designed and synthesized. In vitro testing of this series has led to the identification of several compounds, in particular 2-(nonylsulfonamido)benzoic acid (15g), possessing moderate GPAT inhibitory activity in an intact mitochondrial assay.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acylation
  • Animals
  • Drug Design
  • Drug Evaluation, Preclinical
  • Glycerides / biosynthesis
  • Glycerol-3-Phosphate O-Acyltransferase / antagonists & inhibitors*
  • Glycerophosphates / metabolism
  • Mice
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Obesity / drug therapy*
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology
  • ortho-Aminobenzoates / chemical synthesis*
  • ortho-Aminobenzoates / pharmacology


  • 2-(nonylsulfonamido)benzoic acid
  • Glycerides
  • Glycerophosphates
  • Organophosphonates
  • Sulfonamides
  • ortho-Aminobenzoates
  • alpha-glycerophosphoric acid
  • Glycerol-3-Phosphate O-Acyltransferase