Discovery of 1,3-disubstituted-1H-pyrrole derivatives as potent Melanin-Concentrating Hormone Receptor 1 (MCH-R1) antagonists

A series of 1,3-disubstituted-1H-pyrrole-based antagonists of the human Melanin-Concentrating Hormone Receptor 1 (h-MCH-R1) are reported. High-throughput screening of the AstraZeneca compound collection yielded 1, a hit with moderate affinity towards MCH-R1. Subsequent structural manipulations and SAR analysis served to rationalize potency requirements, and 12 was identified as a novel, functional MCH-R1 antagonist with favorable pharmacokinetic properties.

The optimization of an HTS-derived hit compound into a potent and metabolically stable MCH-R1 antagonist is described.Figure optionsDownload as PowerPoint slide