Structure–activity studies of cyclic ketone inhibitors of the serine protease plasmin: Design, synthesis, and biological activity

Three series of cyclic ketone inhibitors were synthesized and evaluated against the serine protease plasmin. Peptide inhibitors that incorporated 3-oxotetrahydrofuran and 3-oxotetrahydrothiophene 1,1-dioxide groups had the highest activities. Alkylamino substituents, which were designed to bind in the S1 subsite of plasmin, were attached to the inhibitors. Compounds 5c and 5g, which incorporated 6-aminohexyl substituents, were found to be optimal and demonstrated IC50 values in the low micromolar range. Incorporating conformationally constrained peptide segments into the inhibitors did not improve their activities.

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