Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI).
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.
Bondebjerg
Jon
J
Combio A/S, Vesterbrogade 188, DK-1800 Frederiksberg C, Denmark. job@combio.biz
Fuglsang
Henrik
H
Valeur
Kirsten Rosendal
KR
Kaznelson
Dorte Wissing
DW
Hansen
Johnny Arnsdorf
JA
Pedersen
René Orup
RO
Krogh
Berit Olsen
BO
Jensen
Bo Skaaning
BS
Lauritzen
Conni
C
Petersen
Gitte
G
Pedersen
John
J
Naerum
Lars
L
D000818:Animals; D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012663:Semicarbazides / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D012663:Semicarbazides; D020789:Cathepsin C