RESUMEN
A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Inhibidores Enzimáticos/síntesis química , Epóxido Hidrolasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Urea/análogos & derivados , Animales , Humanos , Unión Proteica , Solubilidad , Relación Estructura-Actividad , Urea/químicaRESUMEN
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.