The Discovery of RGH-706, a Highly Efficacious MCH1 Receptor Antagonist, for the Treatment of Obesity and Insatiable Hunger.

The discovery and characterization of a novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole derivative MCH1 receptor antagonist (37) is disclosed. Starting from our previously investigated pyrazino[1,2-a]indole series and utilizing a scaffold hopping strategy, pyrimidine- and 1,4-diazepine-fused indole derivatives were designed and synthesized. Among these, only the prototype molecule containing the 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole scaffold emerged as a chemically stable and potent MCHR1 antagonist. Previous SAR knowledge coupled with an ex vivo occupancy assay helped us to optimize this advanced lead to our candidate (37). The high MCHR1 potency and excellent receptor occupancy profile of 37 translated into statistically significant body weight loss after 14 days in a DIO mice study, supporting the potential use of this compound as a weight loss agent. Compound 37 (RGH-706) has successfully completed a phase I (SAD & MAD) clinical study in the indication of obesity, followed by an exploratory Phase II study in patients with Prader-Willi Syndrome (PWS).