6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease Journal Article
| Authors: | Buckley, B. J.; Majed, H.; Aboelela, A.; Minaei, E.; Jiang, L.; Fildes, K.; Cheung, C. Y.; Johnson, D.; Bachovchin, D.; Cook, G. M.; Huang, M.; Ranson, M.; Kelso, M. J. |
| Article Title: | 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. © 2019 Elsevier Ltd |
| Keywords: | controlled study; human cell; nonhuman; mouse; metastasis; enzyme inhibition; animal experiment; animal model; antineoplastic activity; drug potency; drug structure; drug selectivity; lung metastasis; fibrosarcoma; crystal structure; x ray crystallography; drug binding; chemical reaction; concentration response; chemical modification; mouse model; metastasis inhibition; antimetastatic agent; suzuki reaction; amiloride; cancer; human; article; upa; tryptase; urokinase plasminogen activator; ic50; plasminogen activator inhibitor; anti-metastatic; selective optimisation of side-activity; trypsin-like serine protease; amiloride derivative; guanidinylation |
| Journal Title: | Bioorganic & Medicinal Chemistry Letters |
| Volume: | 29 |
| Issue: | 24 |
| ISSN: | 0960-894X |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2019-12-15 |
| Start Page: | 126753 |
| Language: | English |
| DOI: | 10.1016/j.bmcl.2019.126753 |
| PUBMED: | 31679971 |
| PROVIDER: | scopus |
| PMCID: | PMC7362394 |
| DOI/URL: | |
| Notes: | Source: Scopus |
