Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists

Cannabinoid CB1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed a new series of tetrazole-biarylpyrazoles. The various analogues were efficiently prepared and bio-assayed for binding to cannabinoid CB1 receptor. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, cyclopentyl-tetrazole (9a) demonstrated good binding affinity and selectivity for CB1 receptor (IC50 = 11.6 nM and CB2/CB1 = 366).

Graphical abstractWe have identified a novel tetrazole-based series of small molecule cannabinoid-1 antagonists that shows potency comparable to that of known CB1 antagonists. Among various analogues, cyclopentyl-tetrazole (9a) demonstrated high binding affinity and selectivity for CB1 receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide