Carboxyalkyl dipeptides with atrial natriuretic factor potentiating and antihypertensive activity

Haslanger, Martin F.; Sybertz, Edmund J.; Neustadt, Bernard R.; Smith, Elizabeth M.; Nechuta, Terry; Berger, Joel

doi:10.1021/jm00124a002

Cited by 21 publications

(8 citation statements)

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“…(Stephenson & Kenny, 1987) and atrial dipeptidyl carboxyhydrolase (Harris & Wilson, 1984;Soler & Harris, 1989) catalyse the hydrolysis of the Ser123-Phe124 bond of ANF. These enzymes are not responsible for the activity that we observed, since inclusion of 100 pM-SCH 39370, an endopeptidase-24.11 inhibitor (Haslanger et al, 1989) or of 10 ,/M-captopril, an atrial dipeptidyl carboxyhydrolase (and angiotensin-converting-enzyme) inhibitor, (Harris & Wilson, 1984) in the medium did not affect the generation of 125I-FRY from 125I-hANF by the endothelial cells (G. R. Johnson, L. Arik, B. J. R. Pitts & C. J. Foster, unpublished work).…”

Section: Degradationmentioning

confidence: 66%

Rapid receptor-mediated catabolism of 125I-atrial natriuretic factor by vascular endothelial cells

Johnson¹,

Arik²,

Pitts³

et al. 1990

Biochemical Journal

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The binding, internalization and degradation of 200 pM monoiodinated human atrial natriuretic factor-(99-126) (125I-hANF) by cultured bovine aortic endothelial cells (BAECs) were studied at 37 degrees C. 125I-hANF was rapidly cleared from the extracellular medium (t1/2 approximately 10 min), whereas preincubation of the cells in the presence of 20 mM-NH4Cl or 0.2 mM-chloroquine resulted in a significant inhibition of this process. The BAECs rapidly produce three major degradation products of 125I-hANF, namely [125I]iodotyrosine 126 (125I-Y), Arg125-[125I]iodotyrosine126 (125I-RY) and Phe124-Arg125-[125I]iodotyrosine126(125I-FRY), which were detected in the extracellular medium. NH4Cl and chloroquine acted to inhibit the generation of 125I-Y and 125I-RY, but not that of 125I-FRY. Furthermore, excess unlabelled hANF (300 nM) completely blocked the rapid production of 125I-Y and 125I-RY in the first 5 min, but only partially (49%) inhibited the generation of 125I-FRY. Thus, in contrast with our previous findings with cultured smooth-muscle cells [Johnson, Arik & Foster (1989) J. Biol. Chem. 264, 11637-11642], BAECs bind, internalize and rapidly degrade 125I-hANF, resulting in the release of 125I-Y and 125I-RY into the extracellular medium. Similarly to smooth-muscle cells, the BAECs generate 125I-FRY from 125I-hANF via an extracellular proteolytic event. The rapidity of the receptor-mediated process and its sensitivity to NH4Cl and chloroquine suggest that the 125I-hANF is proteolytically processed in the endosomes of BAECs and that its receptors cycle between the cell surface and intracellular stores.

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Section: Degradationmentioning

confidence: 66%

Rapid receptor-mediated catabolism of 125I-atrial natriuretic factor by vascular endothelial cells

Johnson¹,

Arik²,

Pitts³

et al. 1990

Biochemical Journal

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“…For example, the K\ of (l-carboxy-3-phenylpropyl)Leu-Trp is 5 X 10-8 M for TLN,29 and an analogous compound such as SCH 39370 ((l-carboxy-3-phenylpropyl)Phe-|3-Ala) has a K¡ of 1.1 X 10-8 M for NEP. 30 Taken together, these results seem to indicate that the occupancy of the Si subsite is more important in TLN than in NEP for strong inhibition of the enzyme.…”

Section: Introductionmentioning

confidence: 77%

“…2-Benzyl-4-phenyl-3-butanoic Acid (30). A solution of the mixture 28 and 29 in EtOH was treated with 2 equiv of 1 N NaOH for 3 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

New Thiol Inhibitors of Neutral Endopeptidase EC 3.4.24.11: Synthesis and Enzyme Active-Site Recognition

Gómez-Monterrey¹,

Beaumont²,

Nemecek³

et al. 1994

J. Med. Chem.

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Selective, as well as mixed, inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), are of major clinical interest in the treatment of hypertension and cardiac failure. New thiol inhibitors, corresponding to the general formula HS-CH(R1)-CH2-CH(R2)-CONH-CH(R3)-COOH, were designed in order to explore the putative S1 subsite of the active site of NEP. The inhibitors were also tested on ACE and the most representative on thermolysin (TLN) for comparison. The relatively low inhibitory potencies exhibited by these compounds (IC50S in the 10(-7) M range for NEP and in the 10(-6) M range for ACE) as compared to that of thiorphan (IC50S 2.10 x 10(-9) M on NEP and 1.40 x 10(-7) M on ACE) clearly indicate the absence of the expected energetically favorable interactions with the active site of both peptidases. A 100-fold loss of potency for these inhibitors was also observed for thermolysin as compared to thiorphan. Using the mutated Glu102-NEP, it was possible to demonstrate that the inhibitors do not fit the S1 subsite of NEP but interact with the S'1 and S'2 subsites through binding of their R1 and R2 residues and that the C-terminal amino acid is located outside the active site. These results seem to indicate that these thiol inhibitors are not well adapted for optimal recognition of the S1 subsite of NEP, and probably ACE, and that other zinc-chelating moieties such as carboxylate or phosphonate groups may be preferred for this purpose.

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“…IR (CH2CI2) 1733,1674,1591,1489,1087, 940 cm-1. >H NMR (CDCI3): 8 2.63 (t, 2H), 2.92 (dd, 1H), 3.21-3.41 (m, 3H), 3.55-3.72 (m, 3H), 5.13 (s, 2H), 7.11-7.72 (17) (15.6 g, 24.0 mmol) in ethyl acetate (250 mL) was hydrogenated in a Parr shaker in the presence of palladium on carbon (10%, 9 g) at 50 psi for 5.5 h. The catalyst was filtered off and washed with ethyl acetate (200 mL). After concentration of the filtrate in vacuo, the residue was crystallized from ethyl acetate/hexane (1:1) and the resulting crystalline solid dried under reduced pressure to give 18 (11.49g,86%).…”

Section: Benzyl (/S)-3-[jv-[2-[[(diinethylphosphono)methyl]amino]-3-(...mentioning

confidence: 99%

N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors

S¹,

Erion²,

Tan³

et al. 1994

J. Med. Chem.

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Inhibitors of the zinc protease neutral endopeptidase (NEP, EC 3.4.24.11) offer significant therapeutic interest as antihypertensives due to their ability to potentiate the biological action of the circulating natriuretic hormone ANF (atrial natriuretic factor). N-Phosphonomethyl dipeptides bearing a central (4-phenyl)phenylalanine residue have been designed to exert potent and selective NEP inhibition. In particular, (S)-3-[N-[2- [(phosphonomethyl)amino]-3-(4-biphenylyl)propionyl]amino]propionic acid (10a) (CGS 24592) displayed high inhibitory potency in vitro (IC50 = 1.9 +/- 0.1 nM) and a long plasma half-life in rats but lacked oral bioavailability. This drawback was overcome by using esterase-sensitive (acyloxy)alkyl phosphonates. More remarkable, several diaryl phosphonate derivatives of 10a also performed as effective prodrugs. Specifically, the structurally simple diphenyl phosphonate 18 (CGS 25462) induced potent inhibition of NEP ex vivo for at least 8 h after oral administration to rats (30 mg/kg). Its antihypertensive effect was demonstrated in DOCA-salt rats. At 30 mg/kg orally, 18 caused a significant reduction in mean arterial pressure measuring -35 +/- 7 mmHg at 5-h postdosing. The alpha-aminomethyl phosphonate 18 represents a new generation of selective NEP inhibitors that combine high potency, long duration of action, and oral bioavailability. Therefore, it holds promise as a novel therapeutic agent for the treatment of human hypertension and congestive heart failure.

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Carboxyalkyl dipeptides with atrial natriuretic factor potentiating and antihypertensive activity

Cited by 21 publications

References 1 publication

Rapid receptor-mediated catabolism of 125I-atrial natriuretic factor by vascular endothelial cells

Rapid receptor-mediated catabolism of 125I-atrial natriuretic factor by vascular endothelial cells

New Thiol Inhibitors of Neutral Endopeptidase EC 3.4.24.11: Synthesis and Enzyme Active-Site Recognition

N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors

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