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Highly potent and specific inhibitors of human renin
Author(s) -
Sham Hing L.,
Stein Herman,
Rempel Cheryl A.,
Cohen Jerome,
Plattner Jacob J.
Publication year - 1987
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(87)80834-7
Subject(s) - chemistry , ketone , renin inhibitor , stereochemistry , renin–angiotensin system , scissile bond , hydrolysis , amide , cathepsin , pepsin , pyroglutamic acid , structure–activity relationship , potency , enzyme , biochemistry , active site , amino acid , in vitro , endocrinology , organic chemistry , biology , blood pressure
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 (IC 50 = 3 × 10 −9 , 7 × 10 −9 M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10 −4 M. Comparison of the IC 50 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 Leu 10 —Val 11 amide bond.