RESUMEN

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.

Asunto(s)

Amidas , Piperidinas , Serina Endopeptidasas/efectos de los fármacos , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores del Factor Xa , Humanos , Hígado/enzimología , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Conformación Proteica , Ratas , Proteínas Recombinantes/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Triptasas