Development of irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator.
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.
Joossens
J
J
Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
Van der Veken
P
P
Lambeir
A-M
AM
Augustyns
K
K
Haemers
A
A
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
D001555:Benzene Derivatives; D063065:Organophosphonates; D014568:Urokinase-Type Plasminogen Activator