RESUMEN
Using a dipeptide nitrile scaffold we have identified a potent and selective inhibitor of human dipeptidyl peptidase I.
Asunto(s)
Catepsina C/antagonistas & inhibidores , Dipéptidos/farmacología , Inhibidores Enzimáticos/farmacología , Nitrilos/farmacología , Dipéptidos/síntesis química , Dipéptidos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.1) is a novel putative drug target for the treatment of inflammatory diseases. Using 1 as a starting point (IC50>10 microM), we have improved potency by more than 500-fold and successfully identified novel inhibitors of DPPI via screening of a one-bead-two-compounds library of semicarbazide derivatives. Selected compounds were shown to inhibit intracellular DPPI in RBL-2H3 cells. These compounds were further characterized for adverse effects on HepG2 cells (cytotoxicity and viability) and their metabolic stability in rat liver microsomes was estimated. One of the most potent inhibitors, 8 (IC50=31+/-3 nM; Ki=45+/-2 nM, competitive inhibition), is selective for DPPI over other cysteine and serine proteases, has a half-life of 24 min in rat liver microsomes, shows approximately 50% inhibition of intracellular DPPI at 20 microM and is noncytotoxic.