Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists.

Matteo Gianella-Borradori, Ivy Christou, Carole J R Bataille, Rebecca L Cross, Graham M Wynne, David R Greaves, Angela J Russell

Index: Bioorg. Med. Chem. 23(1) , 241-63, (2014)

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Abstract

The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50<200 nM) and binding affinity (Ki<200 nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.