Abstract
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Alcohol Oxidoreductases / antagonists & inhibitors*
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Alcohol Oxidoreductases / metabolism
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Animals
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Binding Sites
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry*
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Carboxylic Acids / pharmacokinetics
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Computer Simulation
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Humans
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Kidney / enzymology
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Kidney / metabolism
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Liver / enzymology
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Liver / metabolism
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Protein Structure, Tertiary
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / therapeutic use
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Rats
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / therapeutic use
Substances
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Carboxylic Acids
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Enzyme Inhibitors
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Pyrazoles
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Thiophenes
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Alcohol Oxidoreductases
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Hao2 protein, rat