title: Probing the cannabinoid CB1/CB2 receptor subtype selectivity limits of 1,2-diarylimidazole-4-carboxamides by fine-tuning their 5-substitution pattern.
abstract: The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.
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: Martina A W
authors.initials: MA
authors.lastname: van der Neut
authors.forename: Alice J M
authors.initials: AJ
authors.lastname: Borst
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yildirim
authors.forename: Herman H
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: van Vliet
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D000284:Administration, Oral; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D054314:Drug Inverse Agonism; D007022:Hypotension / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D007093:Imidazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013450:Sulfones; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide