Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT)

被引：36

作者：

Harrison, Scott T. ^{[1
]}

Poslusney, Michael S. ^{[1
]}

Mulhearn, James J. ^{[1
]}

Zhao, Zhijian ^{[1
]}

Kett, Nathan R. ^{[1
]}

Schubert, Jeffrey W. ^{[1
]}

Melamed, Jeffrey Y. ^{[1
]}

Allison, Timothy J. ^{[2
]}

Patel, Sangita B. ^{[2
]}

Sanders, John M. ^{[3
]}

Sharma, Sujata ^{[2
]}

Smith, Robert F. ^{[2
]}

Hall, Dawn L. ^{[2
]}

Robinson, Ronald G. ^{[4
]}

Sachs, Nancy A. ^{[4
]}

Hutson, Pete H. ^{[4
]}

Wolkenberg, Scott E. ^{[1
]}

Barrow, James C.

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Global Struct Biol, West Point, PA 19486 USA

[3] Merck Res Labs, Chem Modeling & Informat, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Neurosci Res, West Point, PA 19486 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 03期

关键词：

Catecho O-methyl transferase; schizophrenia; cognition; catechol mimic; MEDICINAL CHEMISTRY; PREFRONTAL CORTEX; SCHIZOPHRENIA; TOLCAPONE; RISK;

D O I：

10.1021/ml500502d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg2+. The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.

引用

页码：318 / 323

页数：6

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