Novel inhibitors of human renin. Cyclic peptides based on the tetrapeptide sequence Glu-D-Phe-Lys-D-Trp.
Cyclic peptide inhibitors of human renin based on a linear peptide, Boc-D-Phe-Cys(Acm)-D-Trp-Leu-OMe (1), were prepared by solution-phase methods. Potent inhibitors were obtained in one series of compounds, Z-Glu-D-Phe-Lys-D-Trp-Leu-OMe (3), in which the D-phenylalanine residue was incorporated in a 15-membered ring structure. Any reductions or enlargements of the ring size led to inactive or less potent peptides. The most potent inhibitor of human renin, Me3CCH2-Glu-D-Phe-Lys-D-Trp-NH(CH2)2CHMe2 (31) (IC50 6.3 x 10(-8) M), was obtained by changing N- and C-terminal parts of pentapeptide 3. It was about 650-fold more potent than linear tetrapeptide I and about 50-fold more potent than cyclic peptide 3. Compound 31 was also 112-fold more potent against human renin than against porcine renin.
ICI Pharmaceuticals, Alderley Park, Macciesfield, Cheshire, U.K.
A S
AS
Dutta
J J
JJ
Gormley
P F
PF
McLachlan
J S
JS
Major
D000595:Amino Acid Sequence; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D000092502:Renin Inhibitors
D009842:Oligopeptides; D010456:Peptides, Cyclic; D000092502:Renin Inhibitors