2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity

  • Bioorg Med Chem Lett. 2011 Jun 1;21(11):3399-403. doi: 10.1016/j.bmcl.2011.03.117.
Dean G Brown  1 ,  Donna L Maier ,  Mark A Sylvester ,  Tiffany N Hoerter ,  Elnaz Menhaji-Klotz ,  Celina C Lasota ,  Lee T Hirata ,  Deidre E Wilkins ,  Clay W Scott ,  Shephali Trivedi ,  Tongming Chen ,  Dennis J McCarthy ,  Carla M Maciag ,  Evelynjeane J Sutton ,  Jerry Cumberledge ,  Don Mathisen ,  John Roberts ,  Anshul Gupta ,  Frank Liu ,  Charles S Elmore ,  Cristobal Alhambra ,  Jennifer R Krumrine ,  Xia Wang ,  Paul J Ciaccio ,  Michael W Wood ,  James B Campbell ,  Magnus J Johansson ,  Jian Xia ,  Xiaotian Wen ,  Ji Jiang ,  Xiaoping Wang ,  Zuozhong Peng ,  Tao Hu ,  Jian Wang
Affiliations
  • 1. CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. [email protected]
PMID: 21524576 DOI: 10.1016/j.bmcl.2011.03.117
Abstract

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA Receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim Depression assay and found to show activity (s.c. 60 mg/kg).