Potent new inhibitors of human renin

@article{Szelke1982PotentNI,
  title={Potent new inhibitors of human renin},
  author={Michael Szelke and Brenda J. Leckie and Allan Hallett and D. Michael Jones and Javier Sueiras and Butrus Atrash and A. F. Lever},
  journal={Nature},
  year={1982},
  volume={299},
  pages={555-557}
}
The renal acid protease renin selectively cleaves its plasma substrate angiotensinogen to release the decapeptide angiotensin I, which in turn is cleaved by a carboxydipeptidase converting enzyme to yield the pressor octapeptide angiotensin II1. It is generally accepted that the renin–angiotensin system has a physiological role in blood pressure and electrolyte homeostasis2, and that abnormalities of the system contribute to certain forms of hypertension3. We previously showed that reduction of… Expand
Novel renin inhibitors containing the amino acid statine
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New highly potent (IC50 = 10−9−10−8 M) competitive inhibitors of renin are reported in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate. Expand
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It could be anticipated that potent and specific renin inhibitors would constitute an interesting alternative to ACEI for two reasons: 1) the first step in the renin-angiotensin system, the hydrolysis of ang Elliotensinogen by renin, is rate limiting; and 2) renin has a unique specificity for angiotens inogen as there is no other known substrate for this enzyme. Expand
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  • Chemistry, Medicine
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  • 1983
TLDR
Three experiments are described using new substrate analogue inhibitors of renin to show that introduction of a reduced isostere in the scissile peptide bond of an analogue greatly increases its ability to inhibit renin of a particular species and substitution of amino acids in the C-terminal adjacent to the scISSile bond influences the affinity and efficacy of substrate analogues as inhibitors. Expand
Inhibitors of renin: present and future.
  • E. Haber
  • Chemistry, Medicine
  • Clinical and experimental hypertension. Part A, Theory and practice
  • 1983
Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogen and peptides thatExpand
Chapter 26. Renin Inhibition
Publisher Summary This chapter discusses the recent progress in the design of renin inhibitors, focusing on in vivo evaluation of these compounds. Renin of the plasma renin-angiotensin system (RAS)Expand
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The results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors. Expand
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  • E. Haber
  • Biology, Medicine
  • American journal of kidney diseases : the official journal of the National Kidney Foundation
  • 1985
TLDR
Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogens, and peptides that are related to the amino-terminal sequence of prorenin. Expand
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The results enhance the possibility of developing renin Inhibitors that can be used clinically, and the parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration ofES 6864. Expand
Is Renin a Factor in the Etiology of Essential Hypertension?
The widespread clinical study of converting-enzyme inhibitors has shown that they are effective antihypertensive drugs even in patients who may manifest either normal or decreased plasma reninExpand
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Chemical modification of the backbone at the cleavage site in the (6-13)-octapeptide of equine angiotensinogen resulted in greatly increased binding affinity and resistance to cleavage by renin. TheExpand
Peptide Inhibitors of the Renin–Angiotensin System
TLDR
This work has studied the effects of synthetic peptides with a leucyl–leucine bond and their derivatives on the activity of renin in the formation of angiotensin. Expand
Specific inhibition of renin by an angiotensinogen analog: studies in sodium depletion and renin-dependent hypertension.
TLDR
This specific in vivo inhibitor of renin can be applied to a wide variety of physiologic studies and is shown to block the pressor response to infused human renin. Expand
Peptide inhibitors of renin angiotensinogen reaction system.
Abstract Methyl or ethyl esters of synthetic tetrapeptides, Leu-Leu-Val-Tyr and Leu-Leu-Val-Phe, acted as competitive inhibitors in the renin renin-substrate reaction system. The chemical structuresExpand
Maintenance of blood pressure by the renin–angiotensin system in normal man
TLDR
The results demonstrate that the renin–angiotensin system maintains blood pressure in these conditions and that the system is an important controller of aldosterone secretion as well as sodium excretion on a normal sodium intake. Expand
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TLDR
Through these actions, the renin-angiotensin system plays an im­ portant role in the regulation of blood pressure and of the volume and composition of the extracellular fluid. Expand
Isorenin, pseudorenin, cathepsin D and renin. A comparative enzymatic study of angiotensin-forming enzymes.
TLDR
It is concluded from the data that isorenin from rat brain and pseudoren in from hog spleen are closely related to, or identical with cathepsin D. Expand
Competitive inhibitors of renin. Inhibitors effective at physiological pH.
TLDR
At physiologic pH (7.5), the inhibitory constants (Ki) increased and solubility decreased to the point that inhibition could not be demonstrated with these peptides, but if leucine-6 was replaced in these peptide with a phenylalanyl or tyrosyl residue, Ki decreased to give effective competitive inhibitors at physiological pH in both buffer and in plasma. Expand
An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody.
TLDR
The expected versatility is demonstrated by giving a detailed account on the measurement of renin concentration and activity in human and rat plasma as well as methods for determination of plasma renin substrate and tissue renin. Expand
KINETICS OF THE REACTION OF RENIN WITH NINE SYNTHETIC PEPTIDE SUBSTRATES
TLDR
The results show that the maximum affinity of the enzyme (lowest Km) for substrate is achieved only with the full tetradecapeptide molecule (asp1-arg2-val3-tyr4-ileu5-his6-pro7-phe8-his9-leu10-leU11-val12-tyR13-ser14). Expand
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