RESUMEN
A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Bazo/enzimología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Mastocitos/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Conformación Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Quinasa Syk , Tiazoles/químicaRESUMEN
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.
Asunto(s)
Hepacivirus/enzimología , Compuestos Macrocíclicos , Quinolinas , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Carbamatos/química , Carbamatos/metabolismo , Hepacivirus/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.
