We have designed and synthesized a series of small peptides containing a perfluoroalkyl ketone group at the C-terminal position of the angiotensin I sequence as inhibitors of human renin. From this series of compounds, 8 and 10 showed strong inhibition of human renin (IC50 = 3 × 10−9, 7 × 10−9 M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10−4 M. Comparison of the IC50 of compound 8 and compound 11 (8.7 × 10−7 M) demonstrated the marked effect of the perfluoropropyl group on the potency of inhibition on renin, presumably due to the strong electron-withdrawing effect causing the ketone in 8 to exist predominantly as the hydrate — thus mimicking the tetrahedral transition state during hydrolysis of the scissile Leu10—Val11 amide bond.
