Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; μ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; μ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
Brugel
Todd A
TA
CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
Smith
Reed W
RW
Balestra
Michael
M
Becker
Christopher
C
Daniels
Thalia
T
Hoerter
Tiffany N
TN
Koether
Gerard M
GM
Throner
Scott R
SR
Panko
Laura M
LM
Folmer
James J
JJ
Cacciola
Joseph
J
Hunter
Angela M
AM
Liu
Ruifeng
R
Edwards
Philip D
PD
Brown
Dean G
DG
Gordon
John
J
Ledonne
Norman C
NC
Pietras
Mark
M
Schroeder
Patricia
P
Sygowski
Linda A
LA
Hirata
Lee T
LT
Zacco
Anna
A
Peters
Matthew F
MF
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004231:Diuresis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D001549:Benzamides; D017473:Receptors, Opioid, kappa; D014326:Tropanes