RESUMEN
To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.
Asunto(s)
Amidinas/síntesis química , Anticoagulantes/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Amidinas/química , Amidinas/metabolismo , Amidinas/farmacología , Animales , Anticoagulantes/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacología , Sitios de Unión , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Factor Xa/química , Factor Xa/metabolismo , Fibrinolíticos/química , Fibrinolíticos/metabolismo , Fibrinolíticos/farmacología , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Tiempo de Protrombina , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trombina/química , Trombina/metabolismo , Trombosis/tratamiento farmacológicoRESUMEN
Cleanroom processing techniques have been used to mass-produce flexible, electroenzymatic glucose sensors designed for implantation in subcutaneous tissue. In vitro characterization studies have shown the sensor's performance to be acceptable. Initial in vivo studies were conducted with the sensor implanted in the subcutaneous tissue of rabbits. Sensors implanted in the subcutaneous tissue of normal human subjects showed an excellent correlation between glucose concentrations measured by the sensor and capillary finger sticks measured with a commercial analyzer.
Asunto(s)
Técnicas Biosensibles , Glucemia/metabolismo , Tejido Conectivo/irrigación sanguínea , Equipos Desechables , Animales , Electrodos Implantados , Humanos , Monitoreo Fisiológico/métodos , Conejos , Reproducibilidad de los ResultadosRESUMEN
A rapid glutamic acid decarboxylase microdilution test for presumptive identification of certain anaerobic bacteria was marketed recently by Carr-Scarborough Microbiologicals, Inc., Stone Mountain, Ga. The test was evaluated with 474 clinical isolates, representing 11 genera and 54 species, and was found to be a useful aid in the presumptive identification of Bacteroides fragilis, B. distasonis, B. vulgatus, B. thetaiotaomicron, B. ovatus, B. uniformis, B. eggerthii, Clostridium perfringens, C. barati, C. sordellii, and Eubacterium limosum.