RESUMO
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.
Assuntos
Compostos de Bifenilo/farmacologia , Ciclobutanos/farmacologia , Receptores de Vitronectina/antagonistas & inibidores , Sulfonamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Compostos de Bifenilo/química , Ciclobutanos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Estrutura Terciária de Proteína , Receptores de Vitronectina/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
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).
Assuntos
Compostos de Bifenilo/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Compostos de Bifenilo/síntese química , Técnicas de Química Combinatória , Integrina alfaVbeta3/antagonistas & inibidores , Ligantes , Modelos Moleculares , Fenilalanina/química , Relação Estrutura-Atividade , Ureia/síntese químicaRESUMO
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.