Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.
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.
Jin
Jian
J
GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. jianjin@unc.edu
Wang
Yonghui
Y
Shi
Dongchuan
D
Wang
Feng
F
Davis
Roderick S
RS
Jin
Qi
Q
Fu
Wei
W
Foley
James J
JJ
Webb
Edward F
EF
Dehaas
Chris J
CJ
Berlanga
Manuela
M
Burman
Miriam
M
Sarau
Henry M
HM
Morrow
Dwight M
DM
Rao
Parvathi
P
Kallal
Lorena A
LA
Moore
Michael L
ML
Rivero
Ralph A
RA
Palovich
Michael
M
Salmon
Michael
M
Belmonte
Kristen E
KE
Busch-Petersen
Jakob
J
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
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D010671:Phenylurea Compounds; D000644:Quaternary Ammonium Compounds; D014443:Tyrosine