Highly potent and specific inhibitors of human renin

Kokubu, Tatsuo; Hiwada, Kunio; Sato, Yumika; Iwata, Takeru; Imamura, Yoichi; Matsueda, Rei; Yabe, Yuichiro; Kogen, Hiroshi; Yamazaki, Mitsuo; Iijima, Yasuteru; Baba, Yoshihiko

doi:10.1016/0006-291x(84)91484-0

Cited by 30 publications

(21 citation statements)

References 18 publications

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“…23 We postulated that small peptides in ANG I sequence with leucinal at the C terminus might be precursors of transition state analogues. Small peptide aldehydes that inhibited human renin were simultaneously reported by us 14 and by Fehrentz et al 24 Tripeptide aldehydes synthesized by Fehrentz et al were more than tenfold less potent than the Z-Phe-His-leucinal we reported. To improve active site binding affinity of small peptide analogues, we replaced the benzene ring of phenylalanine with 1-naphthalene, 2-naphthalene, 9-phenanthrene, or 9-anthracene.…”

Section: Nonesupporting

confidence: 54%

“…When the aldehyde group of leucinal at the C terminus of ES-188 was substituted with an alcohol group, inhibition changed from noncompetitive to competitive. 14 The inhibitory effects of ES-188, ES-226, and ES-254 on six different species of animal renins were studied (Table 2) These three inhibitors demonstrated similar potency in inhibiting monkey and human renin but were about one or two orders of magnitude less active against rabbit renin. They were very weak inhibitors of pig, goat, dog, and rat renins.…”

Section: Nonementioning

confidence: 99%

“…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.…”

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confidence: 99%

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Highly potent and specific inhibitors of human renin.

Kokubu¹,

Hiwada²,

Murakami³

et al. 1985

Hypertension

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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...

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Section: Nonesupporting

confidence: 54%

Section: Nonementioning

confidence: 99%

mentioning

confidence: 99%

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Highly potent and specific inhibitors of human renin.

Kokubu¹,

Hiwada²,

Murakami³

et al. 1985

Hypertension

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“…Incubation temperature, 37 C; excitation wavelength, 340 nm; emission wavelength, 490 nm; excitation bandwidth, 5 nm; emission bandwidth, 10 nm. competitive [29][30][31] and noncompetitive 32) renin inhibitors have also been reported. The K i value obtained for SHA-C14 in this study is higher than some values (< 17:7 mM) that have been reported for synthetic peptides 12,25) but the comparison is not easy to make because our study used a synthetic fluorescent substrate while the previous studies utilized angiotensinogen as the renin substrate.…”

Section: Inhibitory Kineticsmentioning

confidence: 99%

Kinetics of Renin Inhibition by Sodium Houttuyfonate Analogs

Yuan¹,

Wu²,

Aluko³

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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“…The major problem has been the lack of oral activity and insufficient duration of action; renin specificity of the inhibitor is an additional obstacle. Our previous articles 12 " 14 have dealt with highly potent inhibitors of human renin that are small peptide analogues containing statine and that are poorly absorbed. The present report describes an orally active renin inhibitor containing statine analogue, ES 6864, (N-[(2R) -3 -morpholinocarbonyl -2-( 1 -naphthy lmethyOpropionyl] -(4 -thiazolyl) -L -alany 1-cyclostatine -(2-morpholinoethyl)amide).…”

Section: R Enin (Ec 349919) Cleaves Angiotensinogenmentioning

confidence: 99%

A highly potent and long-acting oral inhibitor of human renin.

et al. 1988

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SUMMARY An orally active renin inhibitor, ES 6864 (JV-[(2R)-3-morpholinocarbonyl-2-(l-naphthylmethyl)propionyl]-(4-thiazoIyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a K\ value of 7.3 x 10~9 M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10~5 M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin Inhibitors that can be used clinically. (Hypertension 11: 708-712, 1988) KEY WORDS • human renin inhibitor • competitive inhibition • oral administration marmoset • hog renin-infused rat • plasma renin activity • blood pressure

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Highly potent and specific inhibitors of human renin

Cited by 30 publications

References 18 publications

Highly potent and specific inhibitors of human renin.

Highly potent and specific inhibitors of human renin.

Kinetics of Renin Inhibition by Sodium Houttuyfonate Analogs

A highly potent and long-acting oral inhibitor of human renin.

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