title: SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2.
abstract: 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.
authors: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. todd.brugel@astrazeneca.com
authors: Todd A
authors: TA
authors: Brugel
authors: Reed W
authors: RW
authors: Smith
authors: Michael
authors: M
authors: Balestra
authors: Christopher
authors: C
authors: Becker
authors: Thalia
authors: T
authors: Daniels
authors: Gerard M
authors: GM
authors: Koether
authors: Scott R
authors: SR
authors: Throner
authors: Laura M
authors: LM
authors: Panko
authors: Dean G
authors: DG
authors: Brown
authors: Ruifeng
authors: R
authors: Liu
authors: John
authors: J
authors: Gordon
authors: Matthew F
authors: MF
authors: Peters
mesh_terms: 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
chemical_list: D000928:Antidepressive Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D017473:Receptors, Opioid, kappa; C037689:benzamide