Discovery and development of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.

The melanin-concentrating hormone (MCH) is a hypothalamic peptide that binds to one of two receptors: MCH1 and MCH2. MCH1 is well-recognized for its orexigenic properties but may control a number of other physiological activities from both the CNS and the periphery. MCH2 is not expressed in rodents and so its physiological functions in humans are not well understood. This review highlights the discovery and development of multiple structural classes of MCH1 small-molecule antagonists that show impressive levels of efficacy in rodent models of obesity. In some cases these compounds show improved and more sustained efficacy compared to clinically-approved antiobesity pharmaceutical agents. Despite such compelling efficacy, a number of chemical series are unable to progress to the clinic due to selectivity issues. Ongoing efforts to circumvent these challenges are addressed.