Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists.

Ghrelinplays a major physiological role in the control of food intake, and inverse agonistsof the ghrelinreceptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelinmodulators from high throughput screeningand optimized binding affinity through structure–activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonistactivity to inverse agonistactivity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist22 (AZ-GHS-22) and the CNS penetrant inverse agonist38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.