title: New potent cathepsin G phosphonate inhibitors.
abstract: Cathepsin G is an enzyme with dual chymotrypsin and trypsin-like specificity. As a leukocyte proteinase it is involved in the early stages of the immune response. In this work the synthesis and inhibitory activity of diaryl phosphonic-type irreversible cathepsin G inhibitors are described. Modification of the lead structure Z-Phg(P)(OPh)2 (k(obs)/I=91 M(-1)s(-1)) in phenyl ester moieties followed by incorporation of the basic functional group into the aromatic side chain yielded highly potent cathepsin G inhibitor Z-(4-guanidine)Phg(P)(OC6H4-4-S-Me)2 with the apparent second-order inhibition value at 15,600 M(-1)s(-1). Further elongation of the obtained compound by tripeptide resulted in the inhibitor Ac-Phe-Val-Thr-(4-guanidine)Phg(P)(OC6H4-4-S-Me)2 with the highest k(obs)/I value ever reported in literature (256,000 M(-1)s(-1)).
authors.affiliation: Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspiańskiego 27, 50-370 Wrocław, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Sieńczyk
authors.forename: Adam
authors.initials: A
authors.lastname: Lesner
authors.forename: Magdalena
authors.initials: M
authors.lastname: Wysocka
authors.forename: Anna
authors.initials: A
authors.lastname: Legowska
authors.forename: Ewa
authors.initials: E
authors.lastname: Pietrusewicz
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rolka
authors.forename: Józef
authors.initials: J
authors.lastname: Oleksyszyn
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D063065:Organophosphonates / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D063065:Organophosphonates; D011480:Protease Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G