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).