Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands

Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of oxadiazole-diarylpyrazole 4-carboxamides. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide (12q) and 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC50 = 1.35 nM, CB2/CB1 = 286 for 12q; IC50 = 1.46 nM, CB2/CB1 = 256 for 12r).

We have identified novel oxadiazole-diarylpyrazole 4-carboxamide series of small molecule cannabinoid-1 ligands that show potency comparable to that of known CB1 antagonists. Among various analogs tested, N-phenyl-4-carboxamide (12q) demonstrated high binding affinity for rCB1 receptor.Figure optionsDownload as PowerPoint slide