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 establis...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2005-11, Vol.15 (21), p.4794-4798
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.07.054