Bioorg Med Chem Lett. 2010 Sep 15;20(18):5405-10. Epub 2010 Aug 3.

SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2.

Brugel TA, Smith RW, Balestra M, Becker C, Daniels T, Koether GM, Throner SR, Panko LM, Brown DG, Liu R, Gordon J, Peters MF.

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CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. todd.brugel@astrazeneca.com

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.

PMID:: 20719509; [PubMed - indexed for MEDLINE]

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benzamide

MW: 121.13 g/mol

MF: C₇H₇NO

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SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2.

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