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Sample translations submitted: 1
English to Spanish: PYRIDAZINONA DERIVATIVES THAT INHIBIT ALPHA4 INTEGRINS Detailed field: Chemistry; Chem Sci/Eng
Source text - English FIELD OF THE INVENTION
[0003] The present invention relates to certain novel compounds, methods for preparing compounds, compositions, intermediates and derivatives thereof and for treating integrin mediated disorders. More particularly, the pyridazinone compounds of the present invention are .alpha.4.beta.1 and .alpha.4.beta.7 integrin inhibitors useful for treating integrin mediated disorders.
BACKGROUND OF THE INVENTION
[0004] The present invention relates to pyridazinone derivatives that inhibit .alpha.4 integrins. Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation, and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play a role in both normal and pathophysiological processes. Therefore, the targeting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
[0005] The integrin superfamily is made up of structurally and functionally related glycoproteins consisting of .alpha. and .beta. heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type. .alpha.4.beta.1 ("very late antigen-4" or VLA4) is an integrin expressed on nearly all leukocytes and is a key mediator of the cell-cell and cell-matrix interactions of these cell types. The ligands for .alpha.4.beta.1 include vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin (FN). VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation. VCAM-1 is produced by vascular endothelial cells in response to pro-inflammatory cytokines (A. J. H. Gearing and W. Newman, "Circulating adhesion molecules in disease." Immunol. Today, 14, 506 (1993)). Therefore, .alpha.4.beta.1 has become a therapeutic target for inflammatory conditions.
Translation - Spanish CAMPO DE LA INVENCION
La presente invención se refiere a ciertos compuestos novedosos, métodos para preparar los compuestos, composiciones, intermediarios y derivados de los mismos y para tratar trastornos mediados por integrina. Más particularmente, los compuestos de pirdazinona de la presente invención son inhibidores de integrina 4ß y 4ß7 útiles para tratar trastornos mediados por integrina.
ANTECEDENTES DE LA INVENCION
La presente invención se refiere a derivados de piridazinona que inhiben integrinas -4. Muchos procedimientos fisiológicos requieren que las células se pongan en contacto con otras células y/o matriz extracelular. Dichos eventos de adición pueden ser requeridos para la activación migración proliferación, y diferenciación de células. Las interacciones de célula-célula y célula-matriz están mediadas a través de diversas familias de moléculas de adhesión de célula (CAMs) incluyendo las selectinas, integrinas, caderinas e inmunoglobulinas. CAMs juegan un papel tanto en los procedimientos normales como patofisiológicos. Por consiguiente, la activación de CAMs específicas y relevantes en ciertas condiciones enfermedad sin interferir con las funciones celulares normales es esencial para un agente terapéutico efectivo y seguro inhiba las interacciones de célula-célula y célula-matriz.
La superfamilia de integrina se forma de glicoproteínas estructural y funcionalmente relacionadas consistiendo de heterodimérico y ß, las moléculas del receptor de transmembrana encontraron varias combinaciones casi en cada tipo de célula de mamífero. ß1 (“el antígeno-4 muy atrasado” o VLA-4) es una integrina expresada en casi todos leucocitos y es un mediador clave de las interacciones célula-célula y célula-matriz de estos tipos de células. Los ligandos para 4ß1 incluyen la molécula de adhesión de célula vascular-1 (VCAM-1) y el dominio CS-1 de fibromectina (FN). VCAM-1 es un miembro de la superfamilia Ig y se expresa in vivo en células endoteliales en sitios de inflamación. VCAM-1 se produce a través de las células endoteliales vasculares en respuesta a citocinas pre-inflamatorias (A. J. H. Gearing y W. Newman, "Circulating adhesion molecules in disease." Immunol. Today, 14, 506 (1993)). Por consiguiente, 4ß1 se ha convertido en un objetivo terapéutico para condiciones inflamatorias.
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