title: 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.
authors.affiliation: Combio A/S, Vesterbrogade 188, DK-1800 Frederiksberg C, Denmark. job@combio.biz
authors.forename: Jon
authors.initials: J
authors.lastname: Bondebjerg
authors.forename: Henrik
authors.initials: H
authors.lastname: Fuglsang
authors.forename: Kirsten Rosendal
authors.initials: KR
authors.lastname: Valeur
authors.forename: Dorte Wissing
authors.initials: DW
authors.lastname: Kaznelson
authors.forename: Johnny Arnsdorf
authors.initials: JA
authors.lastname: Hansen
authors.forename: René Orup
authors.initials: RO
authors.lastname: Pedersen
authors.forename: Berit Olsen
authors.initials: BO
authors.lastname: Krogh
authors.forename: Bo Skaaning
authors.initials: BS
authors.lastname: Jensen
authors.forename: Conni
authors.initials: C
authors.lastname: Lauritzen
authors.forename: Gitte
authors.initials: G
authors.lastname: Petersen
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.forename: Lars
authors.initials: L
authors.lastname: Naerum
mesh_terms: 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
chemical_list: D011480:Protease Inhibitors; D012663:Semicarbazides; D020789:Cathepsin C