The　urokinase-type　plasminogen　activator　receptor　(uPAR)　emerges　as　a　key　target　for　anti-metastasis　owing　to　its　pivotal　role　in　facilitating　the　invasive　and　migratory　processes　of　cancer　cells.　Recently,　we　identified　the　uPAR-targeting　anti-metastatic　ability　of　diltiazem　(22),　a　commonly　used　antihypertensive　agent.　Fine-tuning　the　chemical　structures　of　known　hits　represents　a　vital　branch　of　drug　development.　To　develop　novel　anti-metastatic　drugs,　we　performed　an　interface-driven　structural　evolution　strategy　on　22.　The　uPAR-targeting　and　anti-cancer　abilities　of　this　antihypertensive　drug　wereidentified　by　us　recently.　Based　on　in　silico　strategy,　including　extensive　molecular　dynamics　(MD)　simulations,　hierarchical　binding　free　energy　predictions,　and　ADMET　profilings,　we　designed,　synthesized,　and　identified　three　new　diltiazem　derivatives　(221-8,　221-57,　and　221-68)　as　uPAR　inhibitors.　Indeed,　all　of　these　three　derivatives　exhibited　uPAR-depending　inhibitory　activity　against　PC-3　cell　line　invasion　at　micromolar　level.　Particularly,　derivatives　221-68　and　221-8　showed　enhanced　uPAR-dependent　inhibitory　activity　against　the　tumor　cell　invasion　compared　to　the　original　compound.　Microsecond　timesclae　MD　simulations　demonstrated　the　optimized　moiety　of　221-68　and　221-8　forming　more　comprehensive　interactions　with　the　uPAR,　highlighting　the　reasonability　of　our　strategy.　This　work　introduces　three　novel　uPAR　inhibitors,　which　not　only　pave　the　way　for　the　development　of　effective　anti-metastatic　therapeutics,　but　also　emphasize　the　efficacy　and　robustness　of　an　in　silico-based　lead　compound　optimization　strategy　in　drug　design.