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.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Carboxylic Acids/chemistry , Enzyme Inhibitors/chemistry , Pyrazoles/chemistry , Thiophenes/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Liver/metabolism , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/therapeutic use , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic useABSTRACT
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
