From arylureas to biarylamides to aminoquinazolines: Discovery of a novel, potent TRPV1 antagonist

Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.

Graphical abstractA novel VR1 antagonist template (4-aminoquinazoline) exhibits improved in vitro potency and oral bioavailability relative to the corresponding urea or carboxamide compounds.Figure optionsDownload full-size imageDownload as PowerPoint slide