Structure–Affinity Relationships and Structure–Kinetic Relationships of 1,2-Diarylimidazol-4-carboxamide Derivatives as Human Cannabinoid 1 Receptor Antagonists

[Image: see text] We report on the synthesis and biological evaluation of a series of 1,2-diarylimidazol-4-carboxamide derivatives developed as CB(1) receptor antagonists. These were evaluated in a radioligand displacement binding assay, a [(35)S]GTPγS binding assay, and in a competition association assay that enables the relatively fast kinetic screening of multiple compounds. The compounds show high affinities and a diverse range of kinetic profiles at the CB(1) receptor and their structure–kinetic relationships (SKRs) were established. Using the recently resolved hCB(1) receptor crystal structures, we also performed a modeling study that sheds light on the crucial interactions for both the affinity and dissociation kinetics of this family of ligands. We provide evidence that, next to affinity, additional knowledge of binding kinetics is useful for selecting new hCB(1) receptor antagonists in the early phases of drug discovery.