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

Autor:	Michael W. Wood, Dean G. Brown, Shephali Trivedi, Don Mathisen, Mark Sylvester, Xia Wang, John C. Roberts, Zuozhong Peng, Tao Hu, Tiffany N. Hoerter, Magnus Johansson, Donna L. Maier, Tongming Chen, Jennifer R. Krumrine, Ji Jiang, Carla Maciag, Lee T. Hirata, Celina C. Lasota, Anshul Gupta, Deidre E. Wilkins, Frank Liu, Jian Xia, Charles S. Elmore, Evelynjeane J. Sutton, Xiaoping Wang, James B. Campbell, Jerry Cumberledge, Cristobal Alhambra, Dennis J. McCarthy, Elnaz Menhaji-Klotz, Jian Wang, Xiaotian Wen, Paul J. Ciaccio, Clay W Scott
Rok vydání:	2011
Předmět:	Stereochemistry Clinical Biochemistry hERG Pharmaceutical Science Motor Activity Pharmacology Binding Competitive Receptors N-Methyl-D-Aspartate Biochemistry Chemical synthesis Imipramine Inhibitory Concentration 50 Mice chemistry.chemical_compound Drug Discovery medicine Ifenprodil Animals Binding site Molecular Biology Binding Sites Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Antagonist Biological activity Antidepressive Agents chemistry Pyrazines biology.protein Molecular Medicine NMDA receptor Protein Binding medicine.drug
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 21:3399-3403
ISSN:	0960-894X
Popis:	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 (sc 60 mg/kg).
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d39e7b2fa51a028f86ba5dd6fd91511b https://doi.org/10.1016/j.bmcl.2011.03.117 Zobrazit plný text záznamu Full Text from ScienceDirect