3-Amidinophenylalanine-based inhibitors of urokinase

• Published in: Bioorganic & medicinal chemistry letters 1999-11, Vol.9 (21), p.3147-3152
• Main Authors: Stürzebecher, Jörg, Vieweg, Helmut, Steinmetzer, Torsten, Schweinitz, Andrea, Stubbs, Milton T., Renatus, Martin, Wikström, Peter
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Benzamidines - chemical synthesis; Benzamidines - pharmacology; Biological and medical sciences; Chemotherapy; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fibrinolysin - antagonists & inhibitors; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Trypsin Inhibitors - chemical synthesis; Trypsin Inhibitors - pharmacology; Urokinase-Type Plasminogen Activator - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00541-7

Synthesis and anti-uPA activity of a series of Nα-triisopropyl-phenylsulfonyl-protected 3-amidino-phenylalanine 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 K i of 0.41 μM 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. Synthesis and SAR for inhibition of uPA, plasmin and trypsin by a series of Nα-triisopropyl-phenylsulfonyl-protected 3-amidinophenylalanine amides are described. With a K i of 0.41 μM compound 2r is one of the most potent uPA inhibitors described so far. The X-ray structure of 2r was solved in complex with trypsin, superimposed with uPA and suggests an unique binding mode.