Bioorganic and Medicinal Chemistry p. 4408 - 4424 (2005)
Update date:2022-08-04
Topics:
Bondebjerg, Jon
Fuglsang, Henrik
Valeur, Kirsten Rosendal
Kaznelson, Dorte Wissing
Hansen, Johnny Arnsdorf
Pedersen, Rene Orup
Krogh, Berit Olsen
Jensen, Bo Skaaning
Lauritzen, Conni
Petersen, Gitte
Pedersen, John
Naerum, Lars
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 μM), 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 μM and is noncytotoxic.
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