Inhibitors of human renin. Cyclic peptide analogues containing a D-Phe-Lys-D-Trp sequence.
Cyclic peptides containing a D-phenylalanine and a D-tryptophan residue have been synthesized and tested as inhibitors of human renin. Most of these are tripeptide derivatives of the type CO(CH2)3CO-D-Phe-Lys-D-Trp- or COCH2NHCH2CO-D-Phe-Lys-D-Trp- in which the individual side-chain methylene groups have been replaced with -CHMe-, -CMe2-, -CH(Ph)-, -CH(CH2Ph)-, or -CH[CH2)2CHMe2)-groups. The three amino acid residues and the size of the ring were very important features of these compounds. Reducing the ring size gave much less potent compounds. The most potent analogue of the series, CO(CH2)2CHPhCO-D-Phe-Lys-D-Trp-NH(CH2)2CHMe (14, IC50 = 26 nM), was obtained by substituting the methylene group nearer to the D-Phe residue by a -CHPh- group. Compound 14 was 15-fold more potent in inhibiting human renin than porcine renin.
Chemistry Department, ICI Pharmaceuticals, Alderley Park, Macclesfield, 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