Design and synthesis of potent and specific renin inhibitors containing difluorostatine, difluorostatone, and related analogues.

Peptides that contain difluorostatine and difluorostatone residues have been shown to be potent inhibitors of the aspartyl protease renin. The readily hydrated fluoro ketone is proposed to mimic the tetrahedral intermediate that forms during the enzyme-catalyzed hydrolysis of a peptidic bond. It is suggested that the sp3-hybridized ketal acts as a transition-state analogue renin inhibitor. The fluoro ketone is shown to be a much more effective inhibitor than the corresponding nonfluorinated ketone, which acts as a pseudosubstrate. More lipophilic side chains at the P1 site can enhance the inhibitory potency of the difluorostatine analogue, but this cannot be demonstrated in the difluorostatone series. Additionally, high renin specificity has been shown for a difluorostatone-containing peptide.