Donald L. Hertzog and David R. Witty Pages 1455 - 1470 ( 16 )
The pursuit of MCH R1 antagonists for the treatment of obesity has become an active area of research for many pharmaceutical companies. The evidence supporting the use of MCH R1 antagonists for the treatment of obesity is ample, and the recent demonstration of MCH R1 antagonists ’ efficacy in animal models of obesity has served to augment earlier studies involving MCH peptide and transgenic animals. We report herein our search for MCH R1 antagonists from the discovery of a biphenyl amide by high throughput screening, through the optimization of the biphenyl amide to a series of constrained aryl-substituted thienopyrimidinones, and extending the application of the thienopyrimidinone substructure to other series of MCH R1 antagonists. Importantly, these MCH R1 antagonists have demonstrated efficacy in animal models of obesity through once-daily oral administration at low doses.
Melanin-concentrating hormone, MCH, MCH R1, MCH R1 antagonist, obesity
Metabolic and Viral Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27707, USA.