Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists.
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
Lainé
Dramane I
DI
GlaxoSmithKline, Respiratory CEDD, 709 Swedeland Road, P.O. Box 1539, King of Prussia, Pennsylvania 19406-0939, USA. dramane.i.laine@gsk.com
McCleland
Brent
B
Thomas
Sonia
S
Neipp
Christopher
C
Underwood
Brian
B
Dufour
Jeremy
J
Widdowson
Katherine L
KL
Palovich
Michael R
MR
Blaney
Frank E
FE
Foley
James J
JJ
Webb
Edward F
EF
Luttmann
Mark A
MA
Burman
Miriam
M
Belmonte
Kristen
K
Salmon
Michael
M