title: Tyrosine urea muscarinic acetylcholine receptor antagonists: achiral quaternary ammonium groups.
abstract: Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction.
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406-0939, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Roderick S
authors.initials: RS
authors.lastname: Davis
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bullion
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Widdowson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Palovich
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Dulcie B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: Peter T
authors.initials: PT
authors.lastname: Buckley
authors.forename: Edward F
authors.initials: EF
authors.lastname: Webb
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Belmonte
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sarau
authors.forename: Jakob
authors.initials: J
authors.lastname: Busch-Petersen
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects; D051379:Mice; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D014443:Tyrosine; D014508:Urea