3-Amidinophenylalanine-based inhibitors of urokinase.
Synthesis and anti-uPA activity of a series of Nalpha-triisopropyl-phenylsulfonyl-protected 3-amidinophenylalanine amides are described. We have explored SAR around the C-terminal amide part for inhibition of uPA, plasmin and trypsin. Modification of the amide part has been found to affect potency but not selectivity. With a Ki of 0.41 microM 2r-L is one of the most potent uPA inhibitors described so far. The X-ray crystal structure of 2r-L was solved in complex with trypsin, superimposed with uPA and the results suggest an unique binding mode of this inhibitor type.
Stürzebecher
J
J
Zentrum f. Vaskuläre Biologie u. Medizin, Universität Jena, Erfurt, Germany. stuerze@zmkh.ef.uni-jena.de
Vieweg
H
H
Steinmetzer
T
T
Schweinitz
A
A
Stubbs
M T
MT
Renatus
M
M
Wikström
P
P
D001550:Benzamidines / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
D001550:Benzamidines; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014361:Trypsin Inhibitors; D010649:Phenylalanine; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator