RESUMEN
The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.
Asunto(s)
PPAR gamma , PPAR gamma/metabolismo , LigandosRESUMEN
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.
