title: Design and synthesis of small molecule glycerol 3-phosphate acyltransferase inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Remsen Hall, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Wydysh
authors.forename: Susan M
authors.initials: SM
authors.lastname: Medghalchi
authors.forename: Aravinda
authors.initials: A
authors.lastname: Vadlamudi
authors.forename: Craig A
authors.initials: CA
authors.lastname: Townsend
mesh_terms: D000215:Acylation; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005989:Glycerides / Q000096:biosynthesis; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000037:antagonists & inhibitors*; D005994:Glycerophosphates / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C000600612:2-(nonylsulfonamido)benzoic acid; D005989:Glycerides; D005994:Glycerophosphates; D063065:Organophosphonates; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; C029620:alpha-glycerophosphoric acid; D005992:Glycerol-3-Phosphate O-Acyltransferase