Small,Potent,and Selective Diaryl Phosphonate Inhibitors for Urokinase-Type Plasminogen Activator with In Vivo Antimetastatic Properties

摘要

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.