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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 10期

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

页码：3129 / 3133

页数：5

共 23 条

[1]

BRNARDICK EJ, 2009, Patent No. 2009094265

[2]

Metabotropic Glutamate Receptors: Potential Drug Targets for the Treatment of Schizophrenia [J].

Chavez-Noriega, Laura E. ;

Schaffhauser, Herve ;

Campbell, Una C. .

CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2002, 1 (03) :261-281

[3]

Schizophrenia: Moving beyond monoamine antagonists [J].

Conn, P. Jeffrey ;

Tamminga, Carol ;

Schoepp, Darryle D. ;

Lindsley, Craig .

MOLECULAR INTERVENTIONS, 2008, 8 (02) :99-107

[4]

3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2) [J].

Cube, RV ;

Vernier, JM ;

Hutchinson, JH ;

Gardner, MF ;

James, JK ;

Rowe, BA ;

Schaffhauser, H ;

Daggett, L ;

Pinkerton, AB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (09) :2389-2393

[5]

3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization [J].

Duplantier, Allen J. ;

Efremov, Ivan ;

Candler, John ;

Doran, Angela C. ;

Ganong, Alan H. ;

Haas, Jessica A. ;

Hanks, Ashley N. ;

Kraus, Kenneth G. ;

Lazzaro, John T., Jr. ;

Lu, Jiemin ;

Maklad, Noha ;

McCarthy, Sheryl A. ;

O'Sullivan, Theresa J. ;

Rogers, Bruce N. ;

Siuciak, Judith A. ;

Spracklin, Douglas K. ;

Zhang, Lei .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (09) :2524-2529

[6]

Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia [J].

Fraley, Mark E. .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (09) :1259-1275

[7]

SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 5-BENZYL-2-OXAZOLIDONE DERIVATIVES [J].

FUJIMOTO, Y ;

SUZUKI, Y ;

TANAKA, Y ;

TOMINAGA, T ;

TAKEDA, H ;

SEKINE, H ;

MORITO, N ;

MIYAOKA, Y .

HETEROCYCLES, 1977, 6 (9-10) :1604-1609

[8]

GLYCIDYL ETHER REACTIONS WITH URETHANES + UREAS - NEW SYNTHETIC METHOD FOR 2-OXAZOLIDONES [J].

IWAKURA, Y ;

IZAWA, S .

JOURNAL OF ORGANIC CHEMISTRY, 1964, 29 (02) :379-&

[9]

Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers [J].

Jin, CZ ;

Nagasawa, H ;

Shimamura, M ;

Uto, Y ;

Inayama, S ;

Takeuchi, Y ;

Kirk, KL ;

Hori, H .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (18) :4917-4927

[10]

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia [J].

Lieberman, JA ;

Stroup, TS ;

McEvoy, JP ;

Swartz, MS ;

Rosenheck, RA ;

Perkins, DO ;

Keefe, RSE ;

Davis, SM ;

Davis, CE ;

Lebowitz, BD ;

Severe, J ;

Hsiao, JK .

NEW ENGLAND JOURNAL OF MEDICINE, 2005, 353 (12) :1209-1223

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