Asunto(s)
Arteriopatías Oclusivas/complicaciones , Arteria Carótida Interna , Incontinencia Fecal/etiología , Cefalea/etiología , Hemiplejía/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/diagnóstico , Tomografía Computarizada por Rayos X , Arteriopatías Oclusivas/diagnóstico , Arteriopatías Oclusivas/patología , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Enfermedad Crónica , Complicaciones de la Diabetes/complicaciones , Complicaciones de la Diabetes/diagnóstico , Resultado Fatal , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Infarto de la Arteria Cerebral Media/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Cysteinyl-leukotrienes (cysLTs) and thromboxane A(2) (TXA(2)) are important mediators in inflammatory lung diseases such as bronchial asthma and idiopathic pulmonary fibrosis (IPF). We examined the effects of inhaled KP-496, a novel dual antagonist of the cysLTs and TXA(2) receptors, on bleomycin-induced IPF in mice. Mice were intravenously injected bleomycin on day 0, and 0.5% of KP-496 was inhaled twice a day (30 min/time) for the entire experimental period. The effects of KP-496 were evaluated by the number of infiltrated cells in bronchoalveolar lavage fluid (BALF), hydroxyl-L-proline content in the lung, and histopathology. Analyses of BALF on days 7 and 21 revealed that inhaled KP-496 significantly decreased total cell numbers, macrophages, neutrophils, and eosinophils on both days. KP-496 significantly decreased hydroxyl-L-proline content in the lung on day 21. Histopathological analyses of lungs on day 21 demonstrated that KP-496 significantly suppressed inflammatory and fibrotic changes. Our results suggested that the suppression of cysLTs and TXA(2) pathways by KP-496 could control airway inflammation and pulmonary fibrosis, and that KP-496 could be a new therapeutic agent for lung diseases with inflammation and fibrogenesis such as IPF and chronic obstructive pulmonary disease.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzoatos/farmacología , Antagonistas de Leucotrieno/farmacología , Fibrosis Pulmonar/prevención & control , Receptores de Leucotrienos/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Tiazoles/farmacología , Administración por Inhalación , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Benzoatos/administración & dosificación , Bleomicina , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Antagonistas de Leucotrieno/administración & dosificación , Masculino , Ratones , Ratones Endogámicos ICR , Fibrosis Pulmonar/inducido químicamente , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Tiazoles/administración & dosificaciónRESUMEN
The discovery and SAR of 2,3-diphenylpropionic acid derivatives as highly potent VLA-4 antagonists are described. One representative compound, 9cc has inhibited intercellular adhesion by a VCAM-1/VLA-4 interaction with an IC(50) of 1.7 nM, and has good pharmacokinetics and oral bioavailability.