title: Development of irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator.
abstract: In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-d-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A k(app) value in the 10(3) M(-1) s(-1) range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.
authors.affiliation: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Joossens
authors.forename: P
authors.initials: P
authors.lastname: Van der Veken
authors.forename: A-M
authors.initials: AM
authors.lastname: Lambeir
authors.forename: K
authors.initials: K
authors.lastname: Augustyns
authors.forename: A
authors.initials: A
authors.lastname: Haemers
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D001555:Benzene Derivatives; D063065:Organophosphonates; D014568:Urokinase-Type Plasminogen Activator