Highly potent and specific inhibitors of human renin.
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 X 10(-9), 7 X 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 X 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.
D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors; D006801:Humans; D007659:Ketones; D009842:Oligopeptides / Q000494:pharmacology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D002402:Cathepsin D; D004791:Enzyme Inhibitors; D007659:Ketones; D009842:Oligopeptides; D010434:Pepsin A; D000092502:Renin Inhibitors