title: Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity.
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 (approximately 147-fold).
authors.affiliation: Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com
authors.forename: Jos H M
authors.initials: JH
authors.lastname: Lange
authors.forename: Herman H
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Willem
authors.initials: W
authors.lastname: Veerman
authors.forename: Henri C
authors.initials: HC
authors.lastname: Wals
authors.forename: Bob
authors.initials: B
authors.lastname: Stork
authors.forename: Hein K A C
authors.initials: HK
authors.lastname: Coolen
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.forename: Tiny J P
authors.initials: TJ
authors.lastname: Adolfs
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D002186:Cannabinoids / Q000037:antagonists & inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D014961:X-Ray Diffraction
chemical_list: C482795:3-(4-chlorophenyl)-N-methyl-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine; D002186:Cannabinoids; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides