| Literature DB >> 20727752 |
Todd A Brugel1, Reed W Smith, Michael Balestra, Christopher Becker, Thalia Daniels, Tiffany N Hoerter, Gerard M Koether, Scott R Throner, Laura M Panko, James J Folmer, Joseph Cacciola, Angela M Hunter, Ruifeng Liu, Philip D Edwards, Dean G Brown, John Gordon, Norman C Ledonne, Mark Pietras, Patricia Schroeder, Linda A Sygowski, Lee T Hirata, Anna Zacco, Matthew F Peters.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2010 PMID： 20727752 DOI： 10.1016/j.bmcl.2010.07.113
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823