title: Discovery of biphenyl piperazines as novel and long acting muscarinic acetylcholine receptor antagonists.
abstract: A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
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: Brian
authors.initials: B
authors.lastname: Budzik
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: Haibo
authors.initials: H
authors.lastname: Xie
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.forename: Chongye
authors.initials: C
authors.lastname: Zhu
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Edward F
authors.initials: EF
authors.lastname: Webb
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: 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: Dramane I
authors.initials: DI
authors.lastname: Lainé
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D010879:Piperazines; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride