Treatment of Patients with Severe Hypertension by Inhibition of Angiotensin-Converting Enzyme

Johnson, James G.; Black, W. D.; Vukovich, R. A.; Hatch, Fred E.; Friedman, B. I.; Blackwell, C. F.; Shenouda, Andrew; Share, Leonard; Shade, Robert E.; Acchiardo, Sergio R.; Muirhead, E. E.

doi:10.1042/cs048053s

Cited by 14 publications

(12 citation statements)

References 3 publications

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“…To confirm whether the sequenced peptides were in fact EP24.15 substrates, two of the 16 identified peptides (BPP-XIe and BPP-AP) were chemically synthesized. The constant of inhibition (K i values) and relative hydrolysis ratios for these peptides were determined in parallel with known bioactive peptides such as bradykinin, angiotensin I and dynorphin A [1][2][3][4][5][6][7][8][9][10][11][12][13] (Table 2). The peptides BPP-XIe and BPP-AP, selected based on their interaction with the inactive EP24.15, inhibited the hydrolysis of quenched fluorescent substrate by EP24.15, confirming their interaction with the enzyme.…”

Section: Kinetic Parameter Determinationmentioning

confidence: 99%

“…In vitro and in vivo ACE inhibition blocks the generation of angiotensin II (DRVYIHPF) from angiotensin I (DRVYIHPFHL) [5] and the degradation of bradykinin (Bk) [6,7]. These therapeutic properties of ACE inhibitors are largely used to treat hypertension [8–11]. Naturally occurring BPPs with such inhibitory activities were first obtained from the venom of several types of snakes belonging to the Crotalinae subfamily [2,3,12–16].…”

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confidence: 99%

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A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15

et al. 2008

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Characterization of the peptide content of venoms has a number of potential benefits for basic research, clinical diagnosis, development of new therapeutic agents, and production of antiserum. Here, we use a substrate‐capture assay that employs a catalytically inactive mutant of thimet oligopeptidase (EC 3.4.24.15; EP24.15) to identify novel bioactive peptides in Bothrops jararacussu venom. Of the peptides captured with inactive EP24.15 and identified by mass spectrometry, three were previously identified bradykinin‐potentiating peptides (BPP),

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Section: Kinetic Parameter Determinationmentioning

confidence: 99%

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confidence: 99%

A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15

et al. 2008

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“…The in vitro testing results for compounds [1][2][3][4][5][6][7][8][9][10][11][12] as inhibitors of angiotensin-converting enzyme are recorded in Table 1. Inspection reveals that the I50 values depend on the nature of R, X, and Y as defined in the general structure I.…”

Section: Resultsmentioning

confidence: 99%

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

Thorsett¹,

Harris²,

Peterson³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(OXOH-X-CH(CHl)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyldipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = 4CH2 (50% inhibition at 7 nM). Substitution of CH2 or 0 at X and 0 at Y produced significantly less potent inhibitors. Groups shorter or longer than R = 4CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the SI subsite.Angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyldipeptide hydrolase, EC 3.4.15.1) cleaves angiotensin I to the potent vasopressor angiotensin II. It also inactivates the vasodepressor substance bradykinin. The possibility that inhibitors of the enzyme might have clinical importance in the treatment of hypertension has been demonstrated with teprotide (1-3) and more recently by extensive clinical studies using the orally active angiotensin-converting enzyme inhibitor captopril (4). Accordingly, there is much current interest in the synthesis of inhibitors of the enzyme (5, 6).Like thermolysin and carboxypeptidases A and B, angiotensin-converting enzyme contains a zinc atom in its active site (7) that, by analogy, is intimately involved in the cleavage of the scissile carboxamide bond of its substrates. Phosphoramidon (ref. 12 and references cited therein) has shown that the inhibition of metalloproteases by phosphorus compounds may be quite general. Indeed, Holmquist and Vallee (13) recently reported inhibition of angiotensin-converting enzyme by several phosphoramidates, including monophenylphospho-L-phenylalanyl-L-phenylalanine, which exhibited Ki = 1.0 uM. Galardy (14) has reported that phospho-L-alanyl-L-proline is a potent inhibitor of the enzyme and exhibited a Ki of 1.4 nM at pH 7.5.The compounds we shall describe are derivatives of the general structure I. In analogy with the binding ofphosphoramidon to thermolysin, substructure lB is proposed to position itself at the zinc site of the enzyme and to approximate the geometry of a hydrated amide transition state. Substructure UI should then be able to bind in the S, subsite of angiotensin-converting enzyme and corresponds to the R1 substitution so important in the recently described (15) N-carboxymethyldipeptide inhibitors of the enzyme. Substructure IC was chosen because 2-substituted propanoylproline derivatives had been shown to afford very potent inhibitors of angiotensin-converting enzyme (15, 16).MATERIALS AND METHODS A description of our assay procedure has been published (15).2-Methyl-3-phosphonylpropionyl-L-proline (1). d,l-2-Methyl-3-phosphonylpropionic acid (6 g) was stirred with SOC12 (100 ml) overnight at room temperature. Concentration afforded the carboxyl chloride, which was coupled to benzyl L-prolinate hydrochloride (8.4 g) in aqueous dioxane under Sch...

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“…He injected it into some of his hypertensive patients and was delighted to find that the blood pressure was reduced [28,29]. Thus, the concept was proved: angiotensin II was important in hypertension.…”

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confidence: 96%

The history of inhibitors of angiotensin converting enzyme

Vane

2001

ACE Inhibitors

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Treatment of Patients with Severe Hypertension by Inhibition of Angiotensin-Converting Enzyme

Cited by 14 publications

References 3 publications

A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15

A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

The history of inhibitors of angiotensin converting enzyme

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