Metastasis　is　the　cause　of　death　in　the　majority　(similar　to　90%)　of　malignant　cancers.　The　oral　potassium-sparing　diuretic　amiloride　and　its　5-substituted　derivative　5-N,N-(hexamethylene)amiloride　(HMA)　reportedly　show　robust　antitumor/metastasis　effects　in　multiple　in　vitro　and　animal　models.　These　effects　are　likely　due,　at　least　in　part,　to　inhibition　of　the　urokinase　plasminogen　activator　(uPA),　a　key　protease　determinant　of　cell　invasiveness　and　metastasis.　This　study　reports　the　discovery　of　6-substituted　HMA　analogs　that　show　nanomolar　potency　against　uPA,　high　selectivity　over　related　trypsin-like　serine　proteases,　and　minimal　inhibitory　effects　against　epithelial　sodium　channels　(ENaC),　the　diuretic　and　antikaliuretic　target　of　amiloride.　Reductions　in　lung　metastases　were　demonstrated　for　two　analogs　in　a　late-stage　experimental　mouse　metastasis　model,　and　one　analog　completely　inhibited　formation　of　liver　metastases　in　an　orthotopic　xenograft　mouse　model　of　pancreatic　cancer.　The　results　support　further　evaluation　of　6-substituted　HMA　derivatives　as　uPA-targeting　anticancer　drugs.