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.
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.
Wan
Zehong
Z
Respiratory Centre of Excellence for Drug Discovery, Research and Development, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. Zehong.2.Wan@gsk.com
Laine
Dramane I
DI
Yan
Hongxing
H
Zhu
Chongjie
C
Widdowson
Katherine L
KL
Buckley
Peter T
PT
Burman
Miriam
M
Foley
James J
JJ
Sarau
Henry M
HM
Schmidt
Dulcie B
DB
Webb
Edward F
EF
Belmonte
Kristen E
KE
Palovich
Michael
M
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
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