NEW RENIN INHIBITORS CONTAINING NOVEL ANALOGS OF STATINE

Solid-phase methodology has been used to synthesize a series of peptid es 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-P-1' cleavage site. The synthesis of these novel analogues of stati ne together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereoc hemistry of the (3S,4S) Ads was determined by an X-ray crystallographi c analysis of its N gamma-Boc, N beta-Z, R(+)-1-methyl benzamide deriv ative. Peptide Boc-His-Pro-Phe-His-Sta-Val-Ile-His-NH2 (VI) is the bes t inhibitor of human renin containing Sta at position 10. However, pep tides containing Ads and Amd gave better rat renin inhibitors than the corresponding Sta-containing peptides. Peptide Boc-His-Pro-Phe-His-Ad s-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 isoster ic replacement for a dipeptide unit rather than for a single amino aci d residue, in our series of inhibitors Sta is more effective when repl acing only the amino acid at position 10 in the natural angiotensinoge n sequence. None of the peptides gave any effect in vivo in a hyperten sive rat model. (C) Munksgaard 1997.