Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies.
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).
Lange
Jos H M
JH
Solvay Pharmaceuticals, Research Laboratories, CJ van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com
van der Neut
Martina A W
MA
Wals
Henri C
HC
Kuil
Gijs D
GD
Borst
Alice J M
AJ
Mulder
Arie
A
den Hartog
Arnold P
AP
Zilaout
Hicham
H
Goutier
Wouter
W
van Stuivenberg
Herman H
HH
van Vliet
Bernard J
BJ
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
D002186:Cannabinoids; D007093:Imidazoles; D043885:Receptor, Cannabinoid, CB2