title: Selective CB2 receptor agonists. Part 3: the optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model.
abstract: A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bartolozzi
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Pier Francesco
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: 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: 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: 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: Renee
authors.initials: R
authors.lastname: Zindell
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 Pharma GmbH&Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
mesh_terms: D000818:Animals; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D010875:Pipecolic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; 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; D013843:Thiazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D008024:Ligands; D010875:Pipecolic Acids; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013843:Thiazines; C032727:piperidine
keywords: CB1; CB2; Cannabinoid receptor; Metabolic stability; Piperidine; Solubility