RESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration.
Asunto(s)
Compuestos de Bifenilo/farmacología , Ciclobutanos/farmacología , Receptores de Vitronectina/antagonistas & inhibidores , Sulfonamidas/farmacología , Sitios de Unión/efectos de los fármacos , Compuestos de Bifenilo/química , Ciclobutanos/química , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Receptores de Vitronectina/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).
Asunto(s)
Compuestos de Bifenilo/farmacología , Urea/análogos & derivados , Urea/farmacología , Compuestos de Bifenilo/síntesis química , Técnicas Químicas Combinatorias , Integrina alfaVbeta3/antagonistas & inhibidores , Ligandos , Modelos Moleculares , Fenilalanina/química , Relación Estructura-Actividad , Urea/síntesis químicaRESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated as a mechanism for the treatment of restenosis following balloon angioplasty. In this work we present results from screening of a focused combinatorial library based on a biphenyl moiety. Our SAR studies led to the identification of compounds with subnanomolar activity, selectivity towards the related GPIIbIIIa receptor and functional activity on human smooth muscle cell migration.