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

ABSTRACT: 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.

SUBMITTER: Tuttle JB

PROVIDER: S-EPMC4027135 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Tuttle Jamison B JB Anderson Marie M Bechle Bruce M BM Campbell Brian M BM Chang Cheng C Dounay Amy B AB Evrard Edelweiss E Fonseca Kari R KR Gan Xinmin X Ghosh Somraj S Horner Weldon W James Larry C LC Kim Ji-Young JY McAllister Laura A LA Pandit Jayvardhan J Parikh Vinod D VD Rago Brian J BJ Salafia Michelle A MA Strick Christine A CA Zawadzke Laura E LE Verhoest Patrick R PR

ACS medicinal chemistry letters 20121024 1

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 t ...[more]

PMID: 24900560

Dataset Information

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

Publications

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

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