5-Sulfonyl-benzimidazoles as selective CB2 agonists.
A novel series of benzimidazole CB2-receptor agonists was synthesized and the structure-activity relationship explored. The results showed agonistic activities with an EC(50) up to 0.5 nM and excellent selectivity (>4000-fold) over the CB1 receptor. The size of the substituent on the 2-position determined the level of agonism, ranging from inverse agonism to partial agonism to full agonism, which was more pronounced for the rat CB2 receptor. A wide variation of sulfonyl substituents at the benzimidazole 5-position was tolerated, which was used to optimize the drug-like properties. This resulted into lead compound 14j that can be used to investigate the potential of a selective, peripherically acting CB2 agonist. The in vitro profile of key compounds is displayed using pie bar charts (VlaaiVis).
Verbist
Bie M P
BM
Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
De Cleyn
Michel A J
MA
Surkyn
Michel
M
Fraiponts
Erwin
E
Aerssens
Jeroen
J
Nijsen
Marjoleen J M A
MJ
Gijsen
Harrie J M
HJ
D000478:Alkylation; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001562:Benzimidazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013457:Sulfur Compounds; C031000:benzimidazole