4-heterocyclohexanone-based inhibitors of the serine protease plasmin

Three inhibitors that are based upon a 4-heterocyclohexanone nucleus were s ynthesized and evaluated for activity against the serine protease plasmin. Inhibitors of plasmin have potential as cancer chemotherapeutic agents that act by blocking both angiogenesis and metastasis. Inhibitor 1 has moderate activity against plasmin but shows good selectivity for this enzyme compar ed to other serine proteases including trypsin, thrombin, and kallikrein. I nhibitor 2 shows both good activity and selectivity for plasmin. Inhibitor 3, which does not incorporate an aminohexyl group that can interact with th e S1 subsite, has poor activity. These results, along with previous work, d emonstrate that the 4-heterocyclohexanone nucleus can effectively serve as the basis for designing inhibitors of both serine and cyst;eine proteases.