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



Gabriele Murineddu a, *, Battistina Asproni a, Stefania Ruiu b, Francesco Deligia a, Matteo Falzoi b, Amedeo Pau a, Brian F Thomas c, Yanan Zhang c, Gérard A Pinna a, Luca Pani b, #, Paolo Lazzari a, d, *
a Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy
b C.N.R. Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, Italy
c Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, NC 27709, USA
d Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010 Pula (CA), Italy


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© Murineddu et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to these authors at the Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy; Tel: + 39 079 228 749; Fax: + 39 079 228 720; E-mail: muri@uniss.it and at Neuroscienze PharmaNess S.c.a.r.l. Edificio 5, Loc. Piscinamanna, 09100 Pula (CA), Italy; Tel: +390709242026; Fax: +390709242206; E-mail: paolo.lazzari@pharmaness.it
# Currect Affiliation: Italian Drug Agency(AIFA), Via Del Tritone 181, 00187Rome, Italy


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-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.

Keywords: Cannabinoid 2 receptors, Hybridization, In vitro assay, Scaffold hopping, Structure-activity relationships, Tricyclic pyrazoles.