Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions

被引：22

作者：

Tuttle, Jamison B. ^{[1
]}

Anderson, Marie ^{[1
]}

Bechle, Bruce M. ^{[1
]}

Campbell, Brian M. ^{[1
]}

Chang, Cheng ^{[1
]}

Dounay, Amy B. ^{[1
]}

Evrard, Edelweiss ^{[1
]}

Fonseca, Kari R. ^{[1
]}

Gan, Xinmin ^{[1
]}

Ghosh, Somraj ^{[1
]}

Horner, Weldon ^{[1
]}

James, Larry C. ^{[1
]}

Kim, Ji-Young ^{[1
]}

McAllister, Laura A. ^{[1
]}

Pandit, Jayvardhan ^{[1
]}

Parikh, Vinod D. ^{[1
]}

Rago, Brian J. ^{[1
]}

Salafia, Michelle A. ^{[1
]}

Strick, Christine A. ^{[1
]}

Zawadzke, Laura E. ^{[1
]}

Verhoest, Patrick R. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Neurosci Med Chem, Groton, CT 06340 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 01期

关键词：

kynurenine amino transferase; kynurenic acid; aryl hydrocarbon receptor; irreversible inhibition; hydroxamic acid; dose response modeling; in vivo microdialysis; schizophrenia; CATION-PI INTERACTIONS; KYNURENIC ACID; CEREBROSPINAL-FLUID; ELEVATED LEVELS; SCHIZOPHRENIA; RECEPTOR; SITE;

D O I：

10.1021/ml300237v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k(inact)/K-i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.

引用

页码：37 / 40

页数：4

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