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6-Substituted Amiloride Derivatives as Inhibitors of the Urokinase-Type Plasminogen Activator for Use in Metastatic Disease

6-Substituted Amiloride Derivatives as Inhibitors of the Urokinase-Type Plasminogen Activator for Use in Metastatic Disease

Benjamin J Buckley, Hiwa Majed, Ashraf Aboelela, Elahe Minaei, Longguang Jiang, Karen Fildes, Chen-Yi Cheung, Darren Johnson, Daniel Bachovchin, Gregory M Cook, Mingdong Huang, Marie Ranson, Michael J Kelso

Bioorg Med Chem Lett. 2019 Dec 15;29(24):126753.

PMID: 31679971

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, Ki = 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1458011	Amiloride Related Compound A		1458-01-1	Price

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