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,　K-i　=　2.4　mu　M),　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　S1　beta　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.