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
The alpha4beta1 integrin (very late antigen-4, VLA-4) plays an important role in the migration of lymphocytes, monocytes, and eosinophils, but not neutrophils, to sites of inflammation. Pharmacological antagonism of VLA-4 is an attractive prospect for the treatment of predominantly eosinophil mediated diseases such as asthma and allergic rhinitis. We report here on a potent and selective, small molecule VLA-4 inhibitor, (2S)-3-(2', 5'-dichlorobiphenyl-4-yl)-2-({[1-(2-methoxybenzoyl)piperidin-3-yl]carbonyl}amino) propanoic acid, compound 1, and characterize the antagonist activities of this molecule in various cell-based assays and in an animal model of eosinophil migration. Compound 1 inhibited VLA-4/ vascular cell adhesion molecule-1(VCAM-1) interactions with in vitro potencies (IC50 value of 210 nM) in VLA-4-expressing Ramos cells, although the compound did not inhibit cell adhesion to fibronectin via alpha5beta1 integrin (very late antigen-5, VLA-5). Blockade of phorbol-12-myristate-13-acetate (PMA)- or Mn2+-stimulated VLA-4 interactions with compound 1 was observed in human T lymphocytes (IC50 value of 230 nM), human eosinophils (IC50 value of 4.0 microM) and mouse eosinophils (IC50 value of 1.6 microM). Furthermore, compound 1 administered by intraperitoneal injection inhibited eosinophil infiltration in a dose-dependent manner by up to 80% in an air pouch model. These data support the use of small molecule VLA-4 antagonists in the treatment of relevant diseases, such as asthma, atopic dermatitis, or allergic rhinitis.
Asunto(s)
Antialérgicos/farmacología , Antiinflamatorios/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Eosinofilia/prevención & control , Eosinófilos/efectos de los fármacos , Integrina alfa4beta1/antagonistas & inhibidores , Bifenilos Policlorados/farmacología , Enfermedades de la Piel/prevención & control , Animales , Antialérgicos/farmacocinética , Antialérgicos/uso terapéutico , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Adhesión Celular/efectos de los fármacos , Quimiocina CCL11 , Quimiocinas CC , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eosinofilia/inducido químicamente , Eosinofilia/metabolismo , Eosinofilia/fisiopatología , Eosinófilos/metabolismo , Femenino , Fibronectinas/metabolismo , Humanos , Integrina alfa4beta1/metabolismo , Integrina alfa5beta1/metabolismo , Interleucina-5/biosíntesis , Interleucina-5/genética , Células Jurkat , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Bifenilos Policlorados/farmacocinética , Bifenilos Policlorados/uso terapéutico , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/fisiopatología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Acetato de Tetradecanoilforbol , Factores de Tiempo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Terephthalic acid based derivatives containing beta- and gamma-amino acid residues were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the very late antigen 4 (VLA-4) and the vascular cell adhesion molecule 1 (VCAM-1). The compounds 2, 10-12, 14, and 16-17 inhibited the adhesion in a cell based assay in the low and sub micromolar range.
Asunto(s)
Adhesión Celular/efectos de los fármacos , Integrina alfa4beta1/antagonistas & inhibidores , Ácidos Ftálicos/farmacología , Amidas/química , Humanos , Ácidos Ftálicos/química , Urea/química , Molécula 1 de Adhesión Celular Vascular/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.
