RESUMEN
Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/química , Tiazoles/química , Xantina Oxidasa/antagonistas & inhibidores , Administración Oral , Animales , Sitios de Unión , Bovinos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Semivida , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Microsomas Hepáticos , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/uso terapéutico , Ácido Úrico/sangre , Xantina Oxidasa/metabolismoRESUMEN
We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2' and combination of SAR display a >100-fold increase in potency with good cellular activity (IC(50)=0.15microM) relative to the previously reported compound 3.
