Tricyclic Pyrazoles. Part 5. Novel 1,4-Dihydroindeno[1,2-c]pyrazole CB2 Ligands Using Molecular Hybridization Based on Scaffold Hopping.

摘要

In search of new selective CB2 ligands, the synthesis and preliminary biological evaluation of novel\ud1,4-dihydroindeno[1,2-c]pyrazole hybrids of the highly potent prototypicals 5-(4-chloro-3-methylphenyl)-1-(4-\udmethylbenzyl)-N-fenchyl-1H-pyrazole-3-carboxamide 1 and 1-(2,4-dichlorophenyl)-6-methyl-N-(piperidin-1-yl)-1,4-\uddihydroindeno[1,2-c]pyrazole-3-carboxamide 2 are detailed.\udWe postulated that the introduction of those pharmacophoric elements essential for activity of 1 in the tricyclic core of 2\udmight provide CB2 ligands with further improved receptor selectivity and biological activity. Among the compounds,\ud6-chloro-7-methyl-1-(2,4-dichlorophenyl)-N-fenchyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide (22) exhibited low\udtwo digit nanomolar affinity for the cannabinoid CB2R and maintained a high level of CB2-selectivity.