Enkephalinase (EC 3.4.24.11) inhibitors: Protection of endogenous ANF against inactivation and potential therapeutic applications

Schwartz, Jean‐Charles; Gros, Claude P.; Lecomte, Jeanne‐Marie; Bralet, J

doi:10.1016/0024-3205(90)90192-t

Cited by 86 publications

(38 citation statements)

References 106 publications

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“…In this compound, the carbonyl group of the amide bond between Ala and Tyr is absent ; only a methylene group is present ( Figure 1B). This inhibitor was fully stable on incubation with sheep kidney membranes, an enriched source of the proteolytic activity known to degrade cFP [17], under the assay conditions described in the Experimental section. Unfortunately, the potency of this compound towards EP24.15 was less than 1\1000 that of cFP (results not shown).…”

Section: Resultsmentioning

confidence: 99%

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Shrimpton¹,

Abbenante

Lew³

et al. 2000

Biochemical Journal

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Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with α-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a Ki of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

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Section: Resultsmentioning

confidence: 99%

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Shrimpton¹,

Abbenante

Lew³

et al. 2000

Biochemical Journal

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“…15) is a Zn 2+ -containing neutral endopeptidase that is highly concentrated in the brain and testes but is also found in the kidney, heart, lung, and liver. 13 In vitro, it degrades a variety of peptides such as bradykinin, angiotensin I (Ang I), neurotensin, and luteinizing hormone-releasing hormone (LHRH) and converts enkephalin-containing peptides into Leu-and Met-enkephalin. 2 -4 In vivo, 7V-[l-(7?,S)-carboxyl-3-phenylpropylj-Ala-Ala-Phe-p-aminobenzoate (cFP-AAFpAB) blocks degradation of LHRH (a substrate for MEP-24.15); however, its physiological role in the metabolism of vasoactive peptides has not been determined.…”

mentioning

confidence: 99%

Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.

Yang¹,

Saitoh²,

Scicli³

et al. 1994

Hypertension

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/v"-[l-(ft.S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phep-aminobenzoate (cFP-AAF-pAB), an active-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood flow, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to A41-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin converting enzyme inhibitory activity) by metalloendopeptidase-24.11, it is possible that some of its effects are due to angiotensin converting enzyme inhibition. In the present study, we questioned (1) whether cFP-AAF-pAB inhibits angiotensin converting enzyme in vivo and (2) whether cFP-AAF-pAB has renal effects that are independent of its conversion to an angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 junol in 300 pL per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin converting enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/kg), cFP-AAFpAB had no further effect on blood pressure, renal blood flow, or potentiation of the vasodepressor response to bradykinin but still increased glomerular filtration rate by 44±9% (P<.01); urine volume increased by 118±10% (P<.001), urinary sodium excretion by 230±31% (P<.001), urinary potassium excretion by 68±14% (P<.01), and urinary cyclic GMP by 55±18% (P<.01). All of these changes were significant compared with enalaprilat/vehicle-treated rats. Fractional excretion of sodium and potassium did not differ from controls. These results suggest that effects of cFP-AAF-pAB on blood pressure, renal blood flow, and potentiation of the vasodepressor response to bradykinin could be mediated by angiotensin converting enzyme inhibition. However, some of the renal effects may be due to inhibition of metalloendopeptidase-24.15 or peptidases other than angiotensin converting enzyme. Zn 2+ -containing neutral endopeptidase that is highly concentrated in the brain and testes but is also found in the kidney, heart, lung, and liver. 13In vitro, it degrades a variety of peptides such as bradykinin, angiotensin I (Ang I), neurotensin, and luteinizing hormone-releasing hormone (LHRH) and converts enkephalin-containing peptides into Leu-and Met-enkephalin.2 -4 In vivo, 7V-[l-(7?,S)-carboxyl-3-phenylpropylj-Ala-Ala-Phe-p-aminobenzoate (cFP-AAFpAB) blocks degradation of LHRH (a substrate for MEP-24.15); however, its physiological role in the metabolism of vasoactive peptides has not been determined. Genden and Molineaux 5 recently reported that inhibition of MEP-24.15 by cFP-AAF-pAB, an activesite-directed inhibitor, produced a marked fall in mean blood pressure (MBP) that was almost abolished by a kinin receptor antagonist. cFP-AAF-pAB also potentiated the bradykinin-induced vasodepressor response. In preliminary studies, lowers MBP and increases cardiac output, renal blood flow (RBF), and plasma kinins. A recent report 8 states that in vitro cFP-AAF-pAB competitively in...

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“…18 However, the final result is a decrease in blood pressure. 1 - 27 The prevailing hypothesis is that they lower blood pressure by inhibiting the hydrolysis of ANF. However, EP-24.11 is an important kininase, both in the kidney and the brain.…”

Section: Metalloendopeptidase Ec-342415mentioning

confidence: 99%

Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.

Carretero

Scicli

1991

Hypertension

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Inhibitors of two zinc metallopeptidases, angiotensin I converting enzyme (ACE) and neutral metalloendopeptidase-24.11 (EP-24.11), are antihypertensive agents. In this issue of Hypertension, Genden and Molineaux report that yet another peptidase inhibitor, metalloendopeptidase-24.15, EC 3.4.24.15 (EP-24.15), lowers blood pressure in normotensive rats. In this editorial we discuss the possible role of kinins as common mediators of part of the vasodepressor action of these peptidase inhibitors. Genden and Molineaux report that the marked fall in blood pressure caused by the EP-24.15 inhibitor is almost abolished by a kinin receptor antagonist, supporting the hypothesis that kinins play a role in the regulation of normal blood pressure. We have confirmed that the EP-24.15 inhibitor used by these investigators lowers blood pressure. Up to now, EP-24.15 has not been implicated in in vivo metabolism of kinins. Although a number of kininases have been identified, our own previous work indicated that the metabolic pathway responsible for clearing kinins from the circulation involves the action of kininase II (angiotensin I converting enzyme) and renal peptidases. Nevertheless, the main metabolic pathway involved some other unidentified enzyme, since in these experiments disappearance of kinins from the circulation was only marginally reduced by a "cocktail" of inhibitors of ACE, EP-24.11, and carboxypeptidase N. It could be that EP-24.15 is involved in kinin metabolism. However, a number of questions need to be answered with regard to the mechanism by which the EP-24.15 inhibitor lowers blood pressure. The data obtained with the EP-24.15, NE-24.11, and ACE inhibitors suggest that potentiation of vasodilator peptides is yet another possible relevant therapeutic approach to hypertension and perhaps heart failure. (Hypertension 1991;68:366-371)

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Enkephalinase (EC 3.4.24.11) inhibitors: Protection of endogenous ANF against inactivation and potential therapeutic applications

Cited by 86 publications

References 106 publications

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.

Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.

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