title: Design, Synthesis, and Evaluation of 4- and 5-Substitutedo-(Octanesulfonamido)benzoic Acids as Inhibitors of Glycerol-3-Phosphate Acyltransferase.
abstract: Despite a rising demand for anti-obesity therapeutics, few effective pharmacological options are clinically available that target the synthesis and accumulation of body fat. Moderate inhibition of mammalian glycerol-3-phosphate acyltransferase (GPAT) with 2-(alkanesulfonamido)benzoic acids has recently been describedin vitro, accompanied by promising weight lossin vivo.In silicodocking studies with 2-(octanesulfonamido)benzoic acid modeled into the active site of squash GPAT revealed an unoccupied volume lined with hydrophobic residues proximal to C-4 and C-5 of the benzoic acid ring. In an effort to produce more potent GPAT inhibitors, a series of 4- and 5-substituted analogs were designed, synthesized, and evaluated for inhibitory activity. In general, compounds containing hydrophobic substituents at the 4- and 5-positions, such as biphenyl and alkylphenyl hydrocarbons, exhibited an improved inhibitory activity against GPATin vitro. The most active compound, 4-([1,1'-biphenyl]-4-carbonyl)-2-(octanesulfonamido)benzoic acid, demonstrated an IC50of 8.5 µM and represents the best GPAT inhibitor discovered to date. Conversely, further substitution with hydroxyl or fluoro groups, led to a 3-fold decrease in activity. These results are consistent with the presence of a hydrophobic pocket and may support the binding model as a potential tool for developing more potent inhibitors.
authors: Department of Chemistry, The Johns Hopkins University, Remsen Hall, 3400 N. Charles Street, Baltimore, MD 21218, USA.
authors: Victor K
authors: VK
authors: Outlaw
authors: Department of Chemistry, The Johns Hopkins University, Remsen Hall, 3400 N. Charles Street, Baltimore, MD 21218, USA.
authors: Edward A
authors: EA
authors: Wydysh
authors: FASGEN, Inc., UMB Research Park, Building One, 800 W. Baltimore St., Suite 150, Baltimore, MD 21201, USA.
authors: Aravinda
authors: A
authors: Vadlamudi
authors: FASGEN, Inc., UMB Research Park, Building One, 800 W. Baltimore St., Suite 150, Baltimore, MD 21201, USA.
authors: Susan M
authors: SM
authors: Medghalchi
authors: Department of Chemistry, The Johns Hopkins University, Remsen Hall, 3400 N. Charles Street, Baltimore, MD 21218, USA.
authors: Craig A
authors: CA
authors: Townsend