Diarylimidazolyl oxadiazole and thiadiazole derivatives as cannabinoid CB1 receptor antagonists

Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC50 = 1.91 nM) prepared to date.

Graphical abstractWe have identified novel diarylimidazolyl oxadiazole/thiadiazole series of small molecule cannabinoid-1 antagonists that show potency comparable to that of known CB1 antagonists. Among various analogs tested, t-butyl-thiadiazole (10s) demonstrated high binding affinity for rCB1 receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide