title: Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies.
abstract: The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).
authors.affiliation: Solvay Pharmaceuticals, Research Laboratories, CJ 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: Martina A W
authors.initials: MA
authors.lastname: van der Neut
authors.forename: Henri C
authors.initials: HC
authors.lastname: Wals
authors.forename: Gijs D
authors.initials: GD
authors.lastname: Kuil
authors.forename: Alice J M
authors.initials: AJ
authors.lastname: Borst
authors.forename: Arie
authors.initials: A
authors.lastname: Mulder
authors.forename: Arnold P
authors.initials: AP
authors.lastname: den Hartog
authors.forename: Hicham
authors.initials: H
authors.lastname: Zilaout
authors.forename: Wouter
authors.initials: W
authors.lastname: Goutier
authors.forename: Herman H
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: van Vliet
mesh_terms: D000818:Animals; D016466:CHO Cells; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002186:Cannabinoids; D007093:Imidazoles; D043885:Receptor, Cannabinoid, CB2