SYNTHESIS OF PEPTIDYL FLUOROMETHYL KETONES AND PEPTIDYL ALPHA-KETO ESTERS AS INHIBITORS OF PORCINE PANCREATIC ELASTASE, HUMAN NEUTROPHIL ELASTASE, AND RAT AND HUMAN NEUTROPHIL CATHEPSIN-G

Comparison of MeO-Suc-Val-Pro-Phe-C02Me (29) and MeO-Suc-Ala-Ala-Pro-Phe-CO2Me (25) with their corresponding trifluoromethyl ketones 9a and 9b, respectively, in rat and human neutrophil cathepsin G assays showed the a-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was more potent than its corresponding trifluoromethyl ketone (9c) in both porcine pancreatic elastase and human neutrophil elastase assays. Within a set of Ala-Ala-Pro-Val-CF3elastase inhibitors, the carbobenzyloxy (Cbz) N-protecting group conferred greater potency as a P5site recognition unit for elastase than did dansyl, methoxysuccinyl, or terf-butyloxycarbonyl. Initial inhibition of elastase was greater when trifluoromethyl ketone 9f was added from a stock solution of dimethyl sulfoxide than when it had been buffer-equilibrated prior to assay, which suggests that the nonhydrated ketone is the more effective form of the inhibitor. The most potent elastase inhibitor we report is Nα-(Ad-SO2)-Nε-(MeO-Suc)Lys-Pro-Val-CF3(16) which has a Kiof 0.58 nM. © 1990, American Chemical Society. All rights reserved.