New renin inhibitors containing novel analogues of statine

Abstract

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 (3J?, 45)‐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 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 Nγ‐Boc, Nβ‐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. Peptide 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.

Asymmetric Synthesis of anti-Aldol Segments via a Nonaldol Route: Synthetic Applications to Statines and (−)-Tetrahydrolipstatin

“…These statine derivatives have been extensively utilized in the design of aspartyl protease inhibitors, particularly for renin and HIV-1 protease inhibitors. 9–11 The present methodology will provide access to substituted statine derivatives in optically active form.…”

Exploring β-Hydroxy γ-Amino Acids (Statines) in the Design of Hybrid Peptide Foldamers

“…Peptides constituted with statines have been used as protease inhibitors. For example, pepstatin, a naturally occurring peptide, has shown broad inhibitory activities against various aspartic acid proteases, such as pepsin, cathespin D and E, rennin, HIV-1 protease, β-secretase, plasmepsin I and II of the malarial parasite Plasmodium falciparum , etc. In addition, several natural peptides containing statines or modified statines, such as didemnins, dolastatins, hapalosin, tamandarins, etc., displayed promising anticancer properties.…”