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Tricyclic pyrazoles. Part 5. Novel 1,4-dihydroindeno[1,2-c]pyrazole CB2 ligands using molecular hybridization based on scaffold hopping
Murineddu, G., Asproni, B., Ruiu, S., Deligia, F., Falzoi, M., Pau, A., Thomas, B., Zhang, Y., Pinna, G. A., Pani, L., & Lazzari, P. (2012). Tricyclic pyrazoles. Part 5. Novel 1,4-dihydroindeno[1,2-c]pyrazole CB2 ligands using molecular hybridization based on scaffold hopping. The Open Medicinal Chemistry Journal, 6, 1 - 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406267/pdf/TOMCJ-6-1.pdf
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-1H-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.
