Abstract
A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Female
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Guanidines / chemical synthesis*
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Guanidines / chemistry
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Guanidines / pharmacology
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Mammary Neoplasms, Animal / drug therapy*
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Mammary Neoplasms, Animal / pathology
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Models, Molecular
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Neoplasm Metastasis
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Organophosphonates / chemical synthesis*
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Organophosphonates / chemistry
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Organophosphonates / pharmacology
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Rats
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Structure-Activity Relationship
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Guanidines
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Organophosphonates
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methyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-guanidinophenyl)ethylcarbamate
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methyl 1-(diphenoxyphosphoryl)-2-(4-guanidinophenyl)ethylcarbamate
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Urokinase-Type Plasminogen Activator