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

Abstract

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