RESUMEN
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.
Asunto(s)
Oxidorreductasas de Alcohol/antagonistas & inhibidores , Ácidos Carboxílicos/química , Inhibidores Enzimáticos/química , Pirazoles/química , Tiofenos/química , Oxidorreductasas de Alcohol/metabolismo , Animales , Sitios de Unión , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacocinética , Simulación por Computador , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Riñón/enzimología , Riñón/metabolismo , Hígado/enzimología , Hígado/metabolismo , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/uso terapéutico , Ratas , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
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.
