Active site-directed plasmin inhibitors: Extension on the P2 residue.

Abstract Based on the structure of YO-2 [ N -( trans -4-aminomethylcyclohexanecarbonyl)- l -Tyr( O -picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr( O -picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert -butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 { N -( trans -4-aminomethylcyclohexanecarbonyl)- l -Tyr[ O -(quinolin-2-yl)methyl]-NH-octyl} [IC 50  = 0.22 and 77 μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm- 17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.