3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts

被引:39
作者
Brnardic, Edward J. [1 ]
Fraley, Mark E. [1 ]
Garbaccio, Robert M. [1 ]
Layton, Mark E. [1 ]
Sanders, John M. [2 ]
Culberson, Chris [2 ]
Jacobson, Marlene A. [3 ]
Magliaro, Brian C. [3 ]
Hutson, Pete H. [3 ]
O'Brien, Julie A. [4 ]
Huszar, Sarah L. [5 ]
Uslaner, Jason M. [5 ]
Fillgrove, Kerry L. [6 ]
Tang, Cuyue [6 ]
Kuo, Yuhsin [6 ]
Sur, Sylvie M. [7 ]
Hartman, George D. [1 ]
机构
[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA
[2] Merck Res Labs, Dept WP Chem Modeling & Informat, West Point, PA 19486 USA
[3] Merck Res Labs, Dept Psychiat Res, West Point, PA 19486 USA
[4] Merck Res Labs, Dept Vitro Sci, West Point, PA 19486 USA
[5] Merck Res Labs, Dept Cent Pharmacol, West Point, PA 19486 USA
[6] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA
[7] Merck Res Labs, Dept Automated Biotechnol, West Point, PA 19486 USA
关键词
mGluR2; Metabotropic glutamate receptors; Positive allosteric modulator; Schizophrenia; Oxazolidinone; Hit to lead; RECEPTORS; OXAZOLIDINONES; SYSTEM; DRUGS; FACTS;
D O I
10.1016/j.bmcl.2010.03.089
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3129 / 3133
页数:5
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