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ACS Med Chem Lett. 2012 Oct 24;4(1):37-40. doi: 10.1021/ml300237v. eCollection 2013 Jan 10.

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

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Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.


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.


aryl hydrocarbon receptor; dose response modeling; hydroxamic acid; in vivo microdialysis; irreversible inhibition; kynurenic acid; kynurenine amino transferase; schizophrenia

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