Fifteen tripeptide analogues of leupeptin containing either a C-terminal argininal or lysinal were synthesized. The synthetic analogues were tested, using spectrophotometric assay techniques, as inhibitors of trypsin, kallikrein, thrombin, plasmin, and cathepsin B. The lysinal analogues were fairly selective as inhibitors of cathepsin B activity. Acetyl-L-leucyl-L-valyl-L-lysinal (21) showed a stronger inhibition of cathepsin B (IC50 = 4 nanomolar) than leupeptin. Acetyl-L-phenylalanyl-L-valyl-L-argininal (2i) was found to be a good inhibitor of cathepsin B (IC50 = 0.039 microM), thrombin (IC50 = 1.8 microM), and plasmin (IC50 = 2.2 microM).

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New Pepstatin Analogues: Synthesis and Pepsin Inhibition.-Eight diastereomeric tripeptide analogues (VI) and (VII) are prepared from the protected amino acid methyl esters (I) via reduction, coupling with ethyl acetate (III), separation of the diastereomeric hydroxy esters (IV) by high performance liquid chromatography, deprotection, condensation with the mixed anhydride of (V), and final saponification. The analogues are less active than pepstatin as inhibitors of the pepsin hydrolysis of hemoglobin. -(MCCONNELL, R. M.; FRIZZELL, D.; CAMP, A.; EVANS, A.; JONES, W.; CAGLE, C.; J. Med.