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

High Resolution Image Download MS PowerPoint Slide The discovery and characterization of a novel 2,3,4,5-tetrahydro-1 H -[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-1 H -[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).