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1.
Bioorg Med Chem Lett ; 25(2): 367-71, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25466710

RESUMEN

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.


Asunto(s)
Flúor/química , Flúor/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Agammaglobulinemia Tirosina Quinasa , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Relación Estructura-Actividad
2.
J Med Chem ; 58(1): 512-6, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-24712864

RESUMEN

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Isoquinolinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismo
3.
J Med Chem ; 54(7): 2255-65, 2011 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-21375264
4.
Bioorg Med Chem Lett ; 13(23): 4241-4, 2003 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-14623009

RESUMEN

Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.


Asunto(s)
Antiinfecciosos/farmacocinética , Transporte Biológico Activo/efectos de los fármacos , Diaminas/farmacocinética , Plasma/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Diaminas/administración & dosificación , Diaminas/farmacología , Infusiones Intravenosas , Metabolismo de los Lípidos , Masculino , Pruebas de Sensibilidad Microbiana , Ofloxacino/metabolismo , Ofloxacino/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
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