α-Ketoamide Phe—Pro isostere as a new core structure for the inhibition of HIV protease

Abstract

Studies on the inhibition of HIV-1 protease utilizing a core isostere with replacement of the scissle bond for an ga-amino- ketone have resulted in the development of an α-keto-amide isosteric replacement of the Phe—Pro scissle amide bond. The simple dipeptide isostere was shown to be a promising new core structure for the development of the enzyme inhibitors. The K i of this core structure was determined to be 6μM, compared to 230 μ M and > 50 μM for the corresponding phosphinic acid and hydroxyethylamine isosteres.