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6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease. | LitMetric

6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease.

Bioorg Med Chem Lett

School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia. Electronic address:

Published: December 2019

AI Article Synopsis

Article Abstract

The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, K = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted amiloride derivatives were prepared, with multiple examples displaying uPA inhibitory potencies in the nM range. X-ray co-crystal structures revealed that the potency increases relative to amiloride arise from increased occupancy of uPA's S1β subsite by the appended 6-substituents. Leading compounds were shown to have high selectivity over related trypsin-like serine proteases and no diuretic or anti-kaliuretic effects in rats. Compound 15 showed anti-metastatic effects in a xenografted mouse model of late-stage lung metastasis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362394PMC
http://dx.doi.org/10.1016/j.bmcl.2019.126753DOI Listing

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