Abstract
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.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Benzylamines / administration & dosage
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Benzylamines / chemical synthesis
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Benzylamines / pharmacology*
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Injections, Subcutaneous
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Oligopeptides / administration & dosage
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Oligopeptides / chemical synthesis
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Oligopeptides / pharmacology
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Prodrugs / administration & dosage
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Prodrugs / chemical synthesis
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Prodrugs / pharmacokinetics
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Rats
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Benzylamines
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Enzyme Inhibitors
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Oligopeptides
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Prodrugs
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Urokinase-Type Plasminogen Activator