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.

摘要: Comparison of MeO-Suc-Val-Pro-Phe-CO2Me (29) and MeO-Suc-Ala-Ala-Pro-Phe- CO2Me (25) with their corresponding trifluoromethyl ketones 9a 9b, respectively, in rat human neutrophil cathepsin G assays showed the alpha-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was than its ketone (9c) both porcine pancreatic elastase assays. Within a set Ala-Ala-Pro-Val-CF3 inhibitors, carbobenzyloxy (Cbz) N-protecting group conferred greater potency as P5 site recognition unit for did dansyl, methoxysuccinyl, or tert-butyloxycarbonyl. Initial inhibition when 9f added from stock solution dimethyl sulfoxide it had been buffer-equilibrated prior assay, which suggests that nonhydrated is effective form inhibitor. The most inhibitor we report Na-(Ad-SO2)-N epsilon-(MeO-Suc)Lys-Pro-Val-CF3 (16) has Ki 0.58 nM.