α-Ketoamides, α-ketoesters and α-diketones as HCV NS3 protease inhibitors

Peptide-based α-ketoamides, α-ketoesters and α-diketones were designed, synthesized and evaluated against HCV NS3 protease. α-Ketoamides have the highest affinity among the three classes, with 8 being the most potent inhibitor with an IC50 of 340 nM. Scheme 1. (a) (Boc)2O, NaOH, THF/H2O (95%); (b) MeONHMe HCl, BOP, TEA, CH2Cl2 (90%); (c) LAH, THF (91%); (d) Me2C(OH)CN, TEA, CH2Cl2 (81%); (e) HCl, H2O/dioxane; (f) (Boc)2O, Na2CO3, H2O (73% for two steps); (g) allylamine, BOP, DIEA, DMF (82%); (h) 4 N HCl in dioxane; (i) Boc-Asp(t-Bu)-Glu(t-Bu)-Val-Val-Pro-OH (9), BOP, DIEA, DMF (70% for two steps); (j) Dess–Martin oxidation (70%); (k) TFA, CH2Cl2 (95%).