Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies

Jos H M Lange; Martina A W van der Neut; Henri C Wals; Gijs D Kuil; Alice J M Borst; Arie Mulder; Arnold P den Hartog; Hicham Zilaout; Wouter Goutier; Herman H van Stuivenberg; Bernard J van Vliet

doi:10.1016/j.bmcl.2009.12.032

Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1084-9. doi: 10.1016/j.bmcl.2009.12.032. Epub 2009 Dec 11.

Authors

Jos H M Lange¹, Martina A W van der Neut, Henri C Wals, Gijs D Kuil, Alice J M Borst, Arie Mulder, Arnold P den Hartog, Hicham Zilaout, Wouter Goutier, Herman H van Stuivenberg, Bernard J van Vliet

Affiliation

¹ Solvay Pharmaceuticals, Research Laboratories, CJ van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com

PMID: 20031412
DOI: 10.1016/j.bmcl.2009.12.032

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).

Publication types

Comparative Study

MeSH terms

Animals
CHO Cells
Cannabinoids / antagonists & inhibitors
Cannabinoids / metabolism
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Humans
Imidazoles / chemical synthesis*
Imidazoles / metabolism*
Protein Binding / physiology
Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
Receptor, Cannabinoid, CB2 / metabolism*
Structure-Activity Relationship

Substances

Cannabinoids
Imidazoles
Receptor, Cannabinoid, CB2