Lange Jos H M, van Stuivenberg Herman H, Veerman Willem, Wals Henri C, Stork Bob, Coolen Hein K A C, McCreary Andrew C, Adolfs Tiny J P, Kruse Chris G
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
Bioorg Med Chem Lett. 2005 Nov 1;15(21):4794-8. doi: 10.1016/j.bmcl.2005.07.054.
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 (approximately 147-fold).
本文描述了新型3,4-二芳基吡唑啉1作为有效的CB1受体拮抗剂，其亲脂性低于SLV319。关键变化是将原系列中的芳基磺酰基替换为二烷基氨基磺酰基部分。优映体24的绝对构型(4S)通过X射线衍射分析确定，并且在基于CB1受体的模型中，24与利莫那班显示出紧密的分子契合。化合物17在该系列中表现出最高的CB1受体亲和力(Ki = 24 nM)，以及非常强的CB1拮抗活性(pA2 = 8.8)和高CB1/CB2亚型选择性(约147倍)。
