New renin inhibitors containing novel analogues of statine.
Solid-phase methodology has been used to synthesize a series of peptides based on the N-terminal sequence of human angiotensinogen in which statine (Sta) or the novel analogues (3S,4S)-3,4-diamino- or (3R,4S)-3,4-diamino-6-methylheptanoic acid (Ads or R-Ads) and (3S,4S)-4-amino-3-aminomethyl- or (3R,4S)-4-amino-3-aminomethyl-6-methylheptanoic acid (Amd or R-Amd) replace either residue 10 or both residues 10-11 at the P1-P1' cleavage site. The synthesis of these novel analogues of statine together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereochemistry of the (3S,4S) Ads was determined by an X-ray crystallographic analysis of its N gamma-Boc, B beta-Z, R(+)-1-methyl benzamide derivative. Peptide Boc-His-Pro-Phe-His-Sta-Val-Ile-His-NH2 (VI) is the best inhibitor of human renin containing Sta at position 10. However, peptides containing Ads and Amd gave better rat renin inhibitors than the corresponding Sta-containing peptides. Peptides Boc-His-Pro-Phe-His-Ads-Val-Ile-His-NH2 (VII) having Ads at position 10 had an IC50 of 12 nM against rat renin. Although Sta has come to be accepted as an isosteric replacement for a dipeptide unit rather than for a single amino acid residue, in our series of inhibitors Sta is more effective when replacing only the amino acid at position 10 in the natural angiotensinogen sequence. None of the peptides gave any effect in vivo in a hypertensive rat model.
Jones
D M
DM
Ferring Research Institute, Chilworth Research Centre, Southampton, United Kingdom.
Sueiras-Diaz
J
J
Szelke
M
M
Leckie
B J
BJ
Beattie
S R
SR
Morton
J
J
Neidle
S
S
Kuroda
R
R
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D000808:Angiotensinogen / Q000737:chemistry; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D018360:Crystallography, X-Ray; D006538:Heptanoic Acids / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D000092502:Renin Inhibitors
D000596:Amino Acids; D000808:Angiotensinogen; D006538:Heptanoic Acids; D010455:Peptides; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C013165:statine