Highly potent and specific inhibitors of human renin.

Abstract

SUMMARY Small peptide analogues representing the C-terminal portion of angiotensin I sequence were designed as inhibitors of human renin. Among synthesized compounds, benzyloxycarbonyl (-"Z")-O-naphthyl)Ala-His-leucinal (ES-188), Z-(l-naphthyl)Ala-His-statine ethyl ester (ES-226), and Z-(l-naphthyl)Ala-His-statine 2-methylbutylamide (ES-254) markedly inhibited human and primate renins (inhibitory concentration, 50% [IC50], near 10~7 M). These peptide analogues inhibited rabbit renin with one or two orders of magnitude less potency. They were very weak inhibitors of renins from pig, goat, dog, and rat. ES-188 had no discernible effect on cathepsin D, pepsin, or human angiotensin-converting enzyme at the concentration of 10" 4 M. ES-226 had little effect on the three enzymes at the concentration of 10"' M; however, ES-254 had a considerable inhibitory effect on cathepsin D(ICJO of 1.4 x 10" 5 M), pepsin (IC^ of 4.2 x 10" 5 M), and human angiotensin-converting enzyme (ICso of 7.1 x 10" 6 M). Our results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors. (Hypertension 7[Suppl I]: 1-8- [1][2][3][4][5][6][7][8][9][10][11] 1985) KEY WORDS • tripeptide analogues • 1-naphthylalanine • statine R ENIN (EC 3.4.23 15) acts on a protein substrate, angiotensinogen, to release the hemo-. dynamically inactive angiotensin I (ANG I). The ANG I subsequently is converted to the potent pressor peptide angiotensin II (ANG II) by angiotensin-converting enzyme (ACE; EC 3.4.15 1). The development of orally active ACE inhibitors 1 ' 2 and the clear demonstration of their efficacy as antihypertensive drugs in patients with remn-dependent hypertension and essential hypertension 3 " 3 have evoked the interest in the development of potent renin inhibitors that are orally active.In 1968 we reported that methyl or ethyl ester of a tetrapeptide (Leu-Leu-Val-Tyr) in the sequence of equine angiotensinogen acted as a competitive inhibitor of rabbit renin.6 But the inhibitor constant was only in the millimolar range. To develop more potent inhibitors of renin, many analogues of a large segment of renin substrate subsequently have been synthesized, 7 " 10 and inhibitory potency has been improved by replacing the peptide bond (-CO-NH-) at the cleavage site of renin with a reduced bond (-CH 2 -NH-).'' These compounds also have shown a high degree of species specificity.12 Boger and colleagues' 3 tried another approach, incorporating statine into peptide analogues of angiotensinogen. Unfortunately, none of these substrate analogues are orally active.In our preliminary report, 14 we synthesized small peptides in the ANG I sequence, with leucinal at the C terminus, and showed that benzyloxycarbonyl(-"Z")-Phe-His-leucinal and its derivatives were potent inhibitors of human renin in vitro. In this study we report in vitro experiments with derivatives of Z-Phe-Hisleucinal and with new small peptide analogues containing statine that are highly potent and species-specific inhibitors of human renin. were...