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

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 24 Pg. 126753 (12 15 2019) ISSN: 1464-3405 [Electronic] England
• PMID: 31679971 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Diuretics
• Amiloride
• Urokinase-Type Plasminogen Activator

Topics

• Amiloride (analogs & derivatives, pharmacology, therapeutic use)
• Diuretics (pharmacology, therapeutic use)
• Humans
• Neoplasm Metastasis (drug therapy)
• Structure-Activity Relationship
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors)