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.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Aminoimidazole Carboxamide / analogs & derivatives*
-
Aminoimidazole Carboxamide / chemical synthesis
-
Aminoimidazole Carboxamide / chemistry
-
Aminoimidazole Carboxamide / therapeutic use
-
Animals
-
Disease Models, Animal
-
Drug Inverse Agonism
-
Hypotension / drug therapy
-
Imidazoles / chemical synthesis
-
Imidazoles / chemistry*
-
Imidazoles / therapeutic use
-
Mice
-
Rats
-
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
-
Receptor, Cannabinoid, CB1 / metabolism
-
Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
-
Receptor, Cannabinoid, CB2 / metabolism
-
Structure-Activity Relationship
-
Sulfones / chemical synthesis
-
Sulfones / chemistry*
-
Sulfones / therapeutic use
Substances
-
Imidazoles
-
Receptor, Cannabinoid, CB1
-
Receptor, Cannabinoid, CB2
-
Sulfones
-
imidazole-4-carboxamide
-
Aminoimidazole Carboxamide