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 EC50 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).

Graphical abstractSynthesis and exploration of the structure–activity relationship of a novel benzimidazole series as highly selective CB2 agonists are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide