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
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.
Assuntos
Antialérgicos/farmacologia , Anti-Inflamatórios/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinofilia/prevenção & controle , Eosinófilos/efeitos dos fármacos , Integrina alfa4beta1/antagonistas & inibidores , Bifenilos Policlorados/farmacologia , Dermatopatias/prevenção & controle , Animais , Antialérgicos/farmacocinética , Antialérgicos/uso terapêutico , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Adesão Celular/efeitos dos fármacos , Quimiocina CCL11 , Quimiocinas CC , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eosinofilia/induzido quimicamente , Eosinofilia/metabolismo , Eosinofilia/fisiopatologia , Eosinófilos/metabolismo , Feminino , Fibronectinas/metabolismo , Humanos , Integrina alfa4beta1/metabolismo , Integrina alfa5beta1/metabolismo , Interleucina-5/biossíntese , Interleucina-5/genética , Células Jurkat , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Bifenilos Policlorados/farmacocinética , Bifenilos Policlorados/uso terapêutico , Dermatopatias/induzido quimicamente , Dermatopatias/metabolismo , Dermatopatias/fisiopatologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Acetato de Tetradecanoilforbol , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
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.
Assuntos
Adesão Celular/efeitos dos fármacos , Integrina alfa4beta1/antagonistas & inibidores , Ácidos Ftálicos/farmacologia , Amidas/química , Humanos , Ácidos Ftálicos/química , Ureia/química , Molécula 1 de Adesão de Célula Vascular/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.