Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors

被引：12

作者：

Zhao, Zhijian ^{[1
]}

Harrison, Scott T. ^{[1
]}

Schubert, Jeffrey W. ^{[1
]}

Sanders, John M. ^{[2
]}

Polsky-Fisher, Stacey ^{[3
]}

Zhang, Nanyan Rena ^{[3
]}

McLoughlin, Debra ^{[3
]}

Gibson, Christopher R. ^{[3
]}

Robinson, Ronald G. ^{[4
]}

Sachs, Nancy A. ^{[4
]}

Kandebo, Monika ^{[4
]}

Yao, Lihang ^{[4
]}

Smith, Sean M. ^{[4
]}

Hutson, Pete H. ^{[4
]}

Wolkenberg, Scott E. ^{[1
]}

Barrow, James C. ^{[1
,5
]}

机构：

[1] Merck & Co Inc, Med Chem, West Point, PA USA

[2] Merck & Co Inc, Chem Modeling & Informat, West Point, PA USA

[3] Merck & Co Inc, Pharmacokinet Pharmacodynam & Drug Metab, West Point, PA USA

[4] Merck & Co Inc, Neurosci Res, West Point, PA USA

[5] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 12期

关键词：

Catechol O-methyl transferase; Schizophrenia; Cognition; SCHIZOPHRENIA;

D O I：

10.1016/j.bmcl.2016.03.095

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2952 / 2956

页数：5

共 18 条

[1] Biochemical and molecular modeling studies of the O-methylation of various endogenous and exogenous catechol substrates catalyzed by recombinant human soluble and membrane-bound catechol-O-methyltransferases [J].