title: Selective CB2 receptor agonists. Part 1: the identification of novel ligands through computer-aided drug design (CADD) approaches.
abstract: Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: eugene.hickey@boehringer-ingelheim.com.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Hickey
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Zindell
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Pier F
authors.initials: PF
authors.lastname: Cirillo
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Lifen
authors.initials: L
authors.lastname: Wu
authors.affiliation: Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Ermann
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Berry
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
authors.affiliation: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Albrecht
authors.affiliation: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gemkow
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
mesh_terms: D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: Cannabinoid receptor 2; De-novo design; Ligand-based; Proline; Scaffold hopping