SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2.
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated.
Brugel
Todd A
TA
CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. todd.brugel@astrazeneca.com
Smith
Reed W
RW
Balestra
Michael
M
Becker
Christopher
C
Daniels
Thalia
T
Koether
Gerard M
GM
Throner
Scott R
SR
Panko
Laura M
LM
Brown
Dean G
DG
Liu
Ruifeng
R
Gordon
John
J
Peters
Matthew F
MF
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003865:Major Depressive Disorder / Q000188:drug therapy; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D017473:Receptors, Opioid, kappa; C037689:benzamide