Synthesis of Elastase Inhibitors.

摘要

Pulmonary emphysema is currently thought to result from the uninhibited proteolysis of lung tissue by elastase and other proteases. Synthetic inhibitors capable of specifically inhibiting elastase would be expected to be useful reagents both for the treatment of emphysema and for the study of the biological function of elastolytic enzymes. Human leukocyte elastase is irreversibly inhibited by peptide chloromethyl ketones. The peptide chloromethyl ketones Ac-Ala-Ala-Ala-AlaCH2Cl and Ac-Ala-Ala-Pro-AlaCH2Cl were synthesized. Studies of the rate of inhibition of human leukocyte elastase by chloromethyl ketones led to the design and synthesis of Ac-Ala-Ala-Pro-ValCH2Cl and Ac-Ala-Ala-Pro-IleCH2Cl which are 49and 40fold respectively more effective inhibitors than Ac-Ala-Ala-Pro-AlaCH2Cl. Peptide carbazates have been studied as possible elastase inhibitors. Ac-Ala-Ala-Mec-ONp (Mec=NHN(CH3) CO-) acylates elastase within a few seconds with concurrent inhibition of the enzyme.