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-1<i>H</i>-[1,4]diazepino[1,7-<i>a</i>]indole derivative MCH1 receptor antagonist (<b>37</b>) is disclosed. Starting from our previously investigated pyrazino[1,2-<i>a</i>]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<i>H</i>-[1,4]diazepino[1,7-<i>a</i>]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 (<b>37</b>). The high MCHR1 potency and excellent receptor occupancy profile of <b>37</b> 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 <b>37</b> (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).