Rational design, synthesis and biological evaluation of new 1,5-diarylpyrazole derivatives as CB1 receptor antagonists, structurally related to rimonabant

Among cannabinoid type-1 (CB1) receptor antagonists, those developed around the 1,5-diarylpyrazole scaffold of rimonabant (Acomplia™) are the most extensively investigated. In recent years, many SAR and QSAR reports on this topic have been published, focusing on the substitution and orientation of the N1 and C5 aryl functionalities and on the substituents at the 3-carboxamide position. In this context, the purpose of our study was to design and synthesize a set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles strictly related to rimonabant, but with the hydrazide/amide group shifted from position 3 to position 4 of the pyrazole scaffold. The synthesized compounds were evaluated in vitro for their affinity on human CB1 and CB2 (cannabinoid type-2) receptors. Computational studies, performed both in the design step and after biological assays, contributed to rationalize the obtained results in terms of specific molecular interactions between antagonists and the human CB1 receptor.

Graphical abstractA set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles strictly related to rimonabant, but with the hydrazide/amide group shifted from position 3 to position 4 of the pyrazole scaffold was designed, synthesized and evaluated in vitro for their affinity on human CB1 and CB2 receptors. Computational studies contributed to rationalize the obtained results in terms of specific molecular interactions between antagonists and the human CB1 receptor. Figure optionsDownload full-size imageDownload as PowerPoint slide