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.

Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity

“…The mitochondrial GPAT assay has been described (39). As we have done previously (53)(54), isolated mitochondria were added to an incubation mixture with [ 14 C]glycerol-3-phosphate, palmitoyl-CoA, and varying concentrations of FSG67. For the current determinations, the assay was run with or without the sulfhydryl-reactive compound NEM (100 M) to distinguish the NEM-insensitive GPAT1 activity from that of NEM-inactivated GPAT2 (29).…”

“…An earlier evaluation showed that FSG67 had GPAT inhibitory activity in mouse mitochondria (53). We included NEM (100 M) to distinguish the activities of GPAT1 and GPAT2.…”

“…We recently developed small-molecule inhibitors of GPAT whose design was based on the crystalline structure of squash GPAT (53). The compounds had variable inhibitory activity against GPAT in an assay with mouse mitochondrial GPAT, with no NEM.…”

“…The compounds had variable inhibitory activity against GPAT in an assay with mouse mitochondrial GPAT, with no NEM. We have selected a compound with low IC 50 for mitochondrial GPAT activity from those studies (53), herein called FSG67, to investigate the biological consequences of pharmacological GPAT inhibition in mice. The data show that pharmacological GPAT inhibition with FSG67 reduces body weight, adiposity, and food intake in mice, while enhancing fatty acid oxidation and protecting against hypophagia-induced decreases in energy expenditure.…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…34 An insulin sensitizer 30 for the treatment of Type 2 diabetes has been reported. [35][36][37] Amongst these compounds, the most interesting is 29 (MK-0354) which has been the subject of many studies and structural modifications. [38][39][40] A compound for the treatment of ischemic stroke, 31 (a potent pan-JNK inhibitor) 41 and an inhibitor of coagulation to treat thromboembolic disorders 32 (inhibitor of factors IXa and XIa) 42 have been reported.…”