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Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI).

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Bondebjerg J,Fuglsang H,Valeur KR,Kaznelson DW,Hansen JA,Pedersen RO,Krogh BO,Jensen BS,Lauritzen C,Petersen G,Pedersen J,Naerum L

doi

10.1016/j.bmc.2005.04.048

subject

Has Abstract

pub_date

2005-07-15 00:00:00

pages

4408-24

issue

14

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(05)00348-2

journal_volume

13

pub_type

杂志文章

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