Abstract
The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
Keywords:
High-throughput screening; Hit-to-lead; Non-purine XO inhibitors; Pyrimidone; Xanthine oxidase.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Gout Suppressants / chemistry
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Gout Suppressants / pharmacokinetics
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Gout Suppressants / pharmacology
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Gout Suppressants / therapeutic use
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Half-Life
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High-Throughput Screening Assays
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Hyperuricemia / drug therapy
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Magnetic Resonance Spectroscopy
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Molecular Docking Simulation
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Protein Binding
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Protein Structure, Tertiary
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology*
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Pyrimidinones / therapeutic use
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Rats
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Structure-Activity Relationship
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Xanthine Oxidase / antagonists & inhibitors*
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Xanthine Oxidase / metabolism
Substances
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Enzyme Inhibitors
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Gout Suppressants
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Pyrimidinones
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Xanthine Oxidase