title: Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD.
abstract: Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.
authors.affiliation: Respiratory Centre of Excellence for Drug Discovery, Research and Development, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. Zehong.2.Wan@gsk.com
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.forename: Dramane I
authors.initials: DI
authors.lastname: Laine
authors.forename: Hongxing
authors.initials: H
authors.lastname: Yan
authors.forename: Chongjie
authors.initials: C
authors.lastname: Zhu
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Widdowson
authors.forename: Peter T
authors.initials: PT
authors.lastname: Buckley
authors.forename: Miriam
authors.initials: M
authors.lastname: Burman
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sarau
authors.forename: Dulcie B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: Edward F
authors.initials: EF
authors.lastname: Webb
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Belmonte
authors.forename: Michael
authors.initials: M
authors.lastname: Palovich
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C543935:(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo( 3.2.1)octane bromide; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic