Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity

Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (∼147-fold).

Graphical abstractNovel 3,4-diaryldihydropyrazoles 1 as potent CB1 receptor antagonists with lower lipophilicity are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety.Figure optionsDownload full-size imageDownload as PowerPoint slide