title: Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists.
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.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Gianella-Borradori
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Ivy
authors.initials: I
authors.lastname: Christou
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Carole J R
authors.initials: CJ
authors.lastname: Bataille
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Cross
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Wynne
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK. Electronic address: david.greaves@path.ox.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Electronic address: angela.russell@chem.ox.ac.uk.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Russell
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D063386:Cannabinoid Receptor Agonists; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D054852:Small Molecule Libraries
keywords: Agonist; Cannabinoid receptor 1; Cannabinoid receptor 2; Inflammation; Ligand-based screening