title: Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.
abstract: Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany. Electronic address: doris.riether@boehringer-ingelheim.com.
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
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: Lifen
authors.initials: L
authors.lastname: Wu
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Betageri
authors.affiliation: Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Jenkins
authors.affiliation: Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Someina
authors.initials: S
authors.lastname: Khor
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: Eugene R
authors.initials: ER
authors.lastname: Hickey
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: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Albrecht
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ceci
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: Nelamangala V
authors.initials: NV
authors.lastname: Nagaraja
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Romig
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Sauer
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
mesh_terms: D000818:Animals; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011392:Proline / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011392:Proline; D011761:Pyrrolidonecarboxylic Acid
keywords: Cannabinoid receptor 2 (CB2); Metabolic stability; Pharmacokinetic properties; Proline; Solubility