6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease. Issue 24 (15th December 2019)

• Record Type: Journal Article
• Authors: Buckley, Benjamin J.; Majed, Hiwa; Aboelela, Ashraf; Minaei, Elahe; Jiang, Longguang; Fildes, Karen; Cheung, Chen-Yi; Johnson, Darren; Bachovchin, Daniel; Cook, Gregory M.; Huang, Mingdong; Ranson, Marie; Kelso, Michael J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 24(2019)
• Publication Date: 2019-12-15
• Subjects: Urokinase plasminogen activator -- uPA -- Amiloride -- Cancer -- Metastasis -- Anti-metastatic -- Trypsin-like serine protease -- Selective optimisation of side-activity; C1r complement C1r subcomponent -- C1s Complement component 1s -- DDHD1 Phosphatidic acid-preferring phospholipase A1 -- ENaC Epithelial sodium channel -- HMA 5-hexamethyleneamiloride -- HuPA Human urokinase plasminogen activator -- LACTB Serine beta-lactamase-like protein -- MuPA Mouse urokinase plasminogen activator -- PRCP prolylcarboxypeptidase -- SOSA Selective optimization of side-activity -- SAR Structure-activity relationship -- TLSP Trypsin-like serine protease -- uPA Urokinase plasminogen activator -- uPAR Urokinase plasminogen activator receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126753
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.