Author/Authors :
Jos H.M. Lange، نويسنده , , Herman H. van Stuivenberg، نويسنده , , Willem Veerman، نويسنده , , Henri C. Wals، نويسنده , , Bob Stork، نويسنده , , Hein K.A.C. Coolen، نويسنده , , Andrew C. McCreary، نويسنده , , Tiny J.P. Adolfs، نويسنده , , Chris G. Kruse، نويسنده ,
Abstract :
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).
