Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.

@article{Brugel2010DiscoveryO8,
  title={Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.},
  author={Todd A Brugel and Reed W Smith and Michael Balestra and Christopher Becker and Thalia S Daniels and Tiffany N Hoerter and Gerard M Koether and Scott R Throner and Laura M Panko and James J Folmer and Joseph Cacciola and Angela M Hunter and Ruifeng Liu and Philip D Edwards and Dean G Brown and John Gordon and Norman C. LeDonne and Mark R Pietras and Patricia Schroeder and Linda A Sygowski and Lee T Hirata and Anna Zacco and Matthew F. Peters},
  journal={Bioorganic & medicinal chemistry letters},
  year={2010},
  volume={20 19},
  pages={5847-52}
}
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. 

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