Synthesis of Tripeptide Amide Derivatives and Examination of Their Inhibitory Effect on Human Leukocyte Elastase (HLE)

Suc-Tyr-Leu-Val-pNA is a specific substrate for human leukocyte elastase (HLE) and Suc-Tyr-D-Leu-D-Val-pNA is a specific inhibitor of HLE. The p-nitroanilide moiety of the above peptides was replaced by p-acetylaniline, p-benzoylaniline and 4-benzylpiperidine to give Suc-Tyr-Leu-Val-ACA (1), Suc-Tyr-D-Leu-D-Val-ACA (2), Suc-Tyr-Leu-Val-BZA (3), Suc-Tyr-D-Leu-D-Val-BZA (4), Suc-Tyr-Leu-Val-BPP (5) and Suc-Tyr-D-Leu-D-Val-BPP (6), respectively. Tripeptide anilide derivatives (1-4) exhibited stronger inhibitory activity against HLE than the corresponding piperidine amide derivatives (5 and 6). It was found that L-D-D type peptides inhibited HLE competitively and more potently than the corresponding L-L-L type peptides. Suc-Tyr-D-Leu-D-Val-BZA (4) inhibited HLE with a Ki value of 60 μM, whereas Suc-Tyr-Leu-Val-BZA (3) inhibited HLE with a Ki value of 150 μM. although these compounds inhibited HLE more strongly than human leukocyte cathepsin G, peptide (3) inhibited both HLE and catchepsin G with Ki values of 150 and 240 μM, respectively.