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

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

  • Bioorg Med Chem Lett. 2010 Sep 15;20(18):5405-10. doi: 10.1016/j.bmcl.2010.07.112.
Todd A Brugel 1,  Reed W Smith,  Michael Balestra,  Christopher Becker,  Thalia Daniels,  Gerard M Koether,  Scott R Throner,  Laura M Panko,  Dean G Brown,  Ruifeng Liu,  John Gordon,  Matthew F Peters
Affiliations

Affiliation

  • 1 CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. [email protected]
PMID: 20719509 DOI: 10.1016/j.bmcl.2010.07.112
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.

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