Novel renin inhibitors containing the amino acid statine

Abstract

The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

“…Pepstatin derivatives such as lactoyl-pepstatin have Ki values ranging from 4 x 10-10 to 6 x 10-6 M towards human pepsin and gastricsin respectively (Valler et al, 1985a). Similarly, synthetic peptide inhibitors of renin containing statine (Boger et al, 1983) or other non-hydrolysable analogues (Szelke et al, 1982;Hallett et al, 1985), although they do display very effective inhibition of human renin (Ki values approx. 10-9-010 M), nevertheless demonstrate weaker interactions (approx.…”

Isolation of Human Renin Inhibitor from Soybean: Soyasaponin I Is the Novel Human Renin Inhibitor in Soybean

“…Kinetic studies with SRI indicated partial noncompetitive inhibition, with a K i value of 37.5 mM. The renin inhibitors reported to date are mainly peptides, pepstatin-and related compounds, 23,24) except for Aliskiren. 25) No-peptidic inhibitor, Aliskiren, is one of the most potent oral renin inhibitors.…”

Structure of theRhizomucor mieheiaspartic proteinase complexed with the inhibitor pepstatin A at 2.7 Å resolution

“…Both C3 atoms of the statine residues are in the S-con®guration. Previous studies (Rich et al, 1980;Boger et al, 1983;Bailey et al, 1993) suggest that the 3S enantiomers of the statine residue at the P1±P1 H position are much more potent than the 3R enantiomers for pepstatin-type inhibitors. Our present study is consistent with these studies and suggests that RMP is also stereoselective in binding with pepstatin-type inhibitors.…”