Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands

Abstract

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-1 H-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)-1 H-pyrazole-4-carboxamide ( 12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC 50 = 1.35 nM, CB2/CB1 = 286 for 12q; IC 50 = 1.46 nM, CB2/CB1 = 256 for 12r).