Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamidines / chemical synthesis*
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Benzamidines / pharmacology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Fibrinolysin / antagonists & inhibitors
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Phenylalanine / analogs & derivatives*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology
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Trypsin Inhibitors / chemical synthesis
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Trypsin Inhibitors / pharmacology
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
Substances
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Benzamidines
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Enzyme Inhibitors
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Sulfonamides
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Trypsin Inhibitors
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Phenylalanine
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Fibrinolysin
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Urokinase-Type Plasminogen Activator