title: Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.
abstract: High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. jianjin@unc.edu
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Shi
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Roderick S
authors.initials: RS
authors.lastname: Davis
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Edward F
authors.initials: EF
authors.lastname: Webb
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Dehaas
authors.forename: Manuela
authors.initials: M
authors.lastname: Berlanga
authors.forename: Miriam
authors.initials: M
authors.lastname: Burman
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sarau
authors.forename: Dwight M
authors.initials: DM
authors.lastname: Morrow
authors.forename: Parvathi
authors.initials: P
authors.lastname: Rao
authors.forename: Lorena A
authors.initials: LA
authors.lastname: Kallal
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
authors.forename: Michael
authors.initials: M
authors.lastname: Palovich
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Belmonte
authors.forename: Jakob
authors.initials: J
authors.lastname: Busch-Petersen
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D010671:Phenylurea Compounds; D000644:Quaternary Ammonium Compounds; D014443:Tyrosine