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Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions
Jamison B Tuttle1, Marie Anderson1, Bruce M Bechle1
1Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
ACS Medicinal Chemistry Letters
|June 6, 2014
Summary
Researchers discovered new aryl hydroxamates that irreversibly inhibit kynurenine amino transferase II (KAT II), an enzyme linked to psychiatric disorders. A novel interaction led to a potent inhibitor, hydroxamate 4, enhancing drug discovery for neurological conditions.
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibition
- Neuroscience
Background:
- Kynurenine amino transferase II (KAT II) is implicated in psychiatric and neurological disorders, including schizophrenia.
- Irreversible inhibitors offer potential for sustained therapeutic effects.
- Aryl hydroxamates are a class of compounds being explored for enzyme inhibition.
Purpose of the Study:
- To discover and optimize irreversible inhibitors of KAT II.
- To elucidate structure-activity relationships (SAR) for improved potency.
- To identify novel interactions between inhibitors and KAT II.
Main Methods:
- Synthesis of a series of aryl hydroxamate compounds.
- Structure-activity relationship (SAR) studies to guide optimization.
- X-ray crystallography to visualize inhibitor-enzyme interactions.
- Enzyme inhibition assays using k_inact/K_i to assess potency.
Main Results:
- Identification of hydroxamate 4, a disubstituted analogue with significantly enhanced potency.
- Discovery of a novel interaction between hydroxamate 4 and KAT II.
- Demonstration that k_inact/K_i is a critical metric for evaluating inhibitor potency and pharmacodynamic profiles.
- Detailed SAR analysis revealing key structural features for potent inhibition.
Conclusions:
- Aryl hydroxamates are effective irreversible inhibitors of KAT II.
- Hydroxamate 4 represents a promising lead compound due to its potent inhibition and novel binding mode.
- The findings provide a foundation for developing new therapeutics for KAT II-associated neurological and psychiatric disorders.
Keywords:
aryl hydrocarbon receptordose response modelinghydroxamic acidin vivo microdialysisirreversible inhibitionkynurenic acidkynurenine amino transferaseschizophreniaMore Related Videos
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