Discovery of biphenyl piperazines as novel and long acting muscarinic acetylcholine receptor antagonists.
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.
Jin
Jian
J
GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. jianjin@unc.edu
Budzik
Brian
B
Wang
Yonghui
Y
Shi
Dongchuan
D
Wang
Feng
F
Xie
Haibo
H
Wan
Zehong
Z
Zhu
Chongye
C
Foley
James J
JJ
Webb
Edward F
EF
Berlanga
Manuela
M
Burman
Miriam
M
Sarau
Henry M
HM
Morrow
Dwight M
DM
Moore
Michael L
ML
Rivero
Ralph A
RA
Palovich
Michael
M
Salmon
Michael
M
Belmonte
Kristen E
KE
Lainé
Dramane I
DI
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
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D010879:Piperazines; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride