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

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  Publication Details (including relevant citation   information):

Bioorg Med Chem   Lett. 2010 Oct 1;20(19):5847-52. doi:   10.1016/j.bmcl.2010.07.113. Epub 2010 Jul 30.

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

Brugel   TA, Smith RW,   Balestra   M, Becker C,   Daniels   T, Hoerter   TN, Koether   GM, Throner   SR, Panko LM,   Folmer   JJ, Cacciola   J, Hunter   AM, Liu R,   Edwards   PD,Brown DG,   Gordon J,   Ledonne   NC, Pietras   M, Schroeder   P, Sygowski   LA, Hirata   LT, Zacco A,   Peters   MF.

Source

  CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord   Pike, Wilmington, DE 19850, USA.

  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.

  Address (URL): http://www.sciencedirect.com/science/article/pii/S0960894X1100446X

 

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