4-amidinobenzylamine-based inhibitors of urokinase.
A series of 4-amidinobenzylamine-based peptidomimetic inhibitors of urokinase was synthesized. The most potent one, benzylsulfonyl-D-Ser-Ala-4-amidinobenzylamide 16, inhibits uPA with a K(i) of 7.7 nM but is less selective than 10 with a Gly as P2 residue. Hydroxyamidine and carbonate prodrugs were prepared, which are rapidly converted into the active inhibitors in rats after subcutaneous application.
Künzel
Sebastian
S
Institut fur Biochemie und Biophysik, Universitat Jena, Philosophenweg 12, D-07743, Jena, Germany.
Schweinitz
Andrea
A
Reissmann
Siegmund
S
Stürzebecher
Jörg
J
Steinmetzer
Torsten
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001596:Benzylamines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D007279:Injections, Subcutaneous; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011355:Prodrugs; D014568:Urokinase-Type Plasminogen Activator