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Biomedical subjects

A Y Jeng

Publications and source records attributed to A Y Jeng.

At least 37 records · Page 2Linked to original sources
PubMed2000

Attenuation of puromycin aminonucleoside-induced glomerular lesions in rats by CGS 26303, a dual neutral endopeptidase/endothelin-converting enzyme inhibitor.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of various renal diseases. The purpose of this study was to investigate the effect of CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, on puromycin aminonucleoside (PA)-induced nephrosis in rats. The animals (three groups; n = 8 per group) received 50 mg/kg PA or NaCl, intravenously. CGS 26303 (5 mg/kg/day, s.c. via osmotic minipumps) or vehicle was administered to the PA-treated animals for 4 weeks, starting within 5 min after PA injection. Uninephrectomy was performed 2 weeks after PA to accelerate the renal damage. Rats received no treatment between 4 and 8 weeks. At 8 weeks rats were euthanized and kidneys removed for histology and analysis for mRNA levels of endothelin-A- and -B- (ET(A) and ET(B)) receptors and ECE-1. Glomeruli (100 glomeruli/section; 800/group) were graded as normal (N), mild lesion (ML = few periodic acid-Schiff positive [PAS+] droplets and small adhesions to Bowman's capsule), and moderate to severe lesion (SL = many PAS+ droplets, adhesions to and thickening of Bowman's capsule, mesangial expansion, and cystic dilations of glomerular capillaries). In the PA + vehicle group N, ML and SL were 39.5%, 11.9% and 48.6%, respectively, while the respective values were 68.3%, 9.4%, and 22.3% in PA + CGS 26303-treated rats. However, the renal mRNA levels of ECE-1 and ET(A)- and ET(B)-receptors were not significantly different among the three groups. These results confirm the efficacy of ECE inhibition in this disease model. On the other hand, the mRNA data suggest that either there was no change in the expression of the genes examined or their levels had already returned to normal by the end of the experiment.

Animals↗
PubMed2000

Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats.

The gene expression and levels of endothelins (ETs) are increased in various animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodynamic and haematological disturbances, organ injury and circulatory failure in ENDO. Previous studies using ET(A)- and/or ET(B)-receptor antagonists exacerbated the effects of LPS in anaesthetized and conscious rats. We investigated the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mixed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-induced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injection, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. In addition, progressive liver dysfunction, characterized by increases in plasma bilirubin and alanine transferase, became even more apparent (higher than in those injected with LPS). Plasma creatinine and blood urea were similar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-induced deleterious effects.

Acid-Base Equilibrium↗
PubMed1999

Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP-13 and on restenosis in rats after balloon injury.

The broad-spectrum MMP inhibitor CGS 27023A was tested to determine its potential as a therapy for atherosclerosis, aneurysm, and restenosis. LDL receptor-deficient (LDLr -/-) mice fed a high-fat, cholic acid-enriched diet for 16 weeks developed advanced aortic atherosclerosis with destruction of elastic lamina and ectasia in the media underlying complex plaques. Lesion formation correlated with a 4.6- to 21.7-fold increase in MMP-3, -12, and -13 expression. Treatment with CGS 27023A (p.o., b.i.d. at 50 mg/kg) had no effect on the extent of aortic atherosclerosis (36 +/- 4% versus 30 +/- 2% in controls), but both aortic medial elastin destruction and ectasia grade were significantly reduced (38% and 36%, respectively, p < 0.05). In the rat ballooned-carotid-artery model, CGS 27023A (12.5 mg/kg/day via osmotic minipump) reduced smooth muscle cell migration at 4 days by 83% (p < 0.001). Intimal lesions were reduced by 85% at 7 days (p < 0.001), but intimal smooth muscle proliferation was unaffected, and inhibitory efficacy was lost with time. At 12 days, intimal lesion reduction was less potent (52%, p < 0.01). At 3 and 6 weeks, reductions of 11% and 4%, respectively, were not significant. This demonstrates that it is essential to include late time points when the ballooned-carotid-artery model is employed to ensure that lesion size does not "catch up" when a compound solely inhibits smooth muscle cell migration. In summary, MMP inhibitor therapy delayed but did not prevent intimal lesions, thereby demonstrating little promise to prevent restenosis. In contrast, MMP inhibitor therapy may prove useful to retard progression of aneurysm.

Animals↗
PubMed1999

Endothelin converting enzyme-1-, endothelin-1-, and endothelin-3-like immunoreactivity in the rat brain.

Neurons likely to use endothelin as a neurotransmitter/neurohormone were mapped in the rat brain using polyclonal antibodies directed against endothelin-converting enzyme-1, endothelin-1, and endothelin-3. Anti-endothelin-converting enzyme-1 antibodies produced the most robust staining, permitting the best visualization of the distribution and morphology of neurons. Labeled neurons were found in the dorsal thalamic nuclei and reticular thalamic nuclei, medial preoptic area, pontine nucleus, and locus coeruleus. Localization of endothelin-converting enzyme-like immunoreactivity in the locus coeruleus and in the reticular nucleus of the thalamus suggests that endothelin is co-localized with norepinephrine and GABA, respectively. Additionally, endothelin-converting enzyme-like immunoreactivity was found in the globus pallidus, septal nuclei, and in both the vertical and horizontal limbs of the nucleus of the diagonal band of Broca, and the ventrolateral area of the caudate-putamen. Strong endothelin-converting enzyme-like immunoreactivity was found in a continuous band of pyramidal neurons throughout the neocortex primarily in layer V, extending into the cingulate gyrus and piriform cortex. Motor nuclei, including oculomotor, facial, and trigeminal nuclei, were also endothelin-converting enzyme-immunoreactive. In the cerebellum, Purkinje cells were stained. Non-neuronal cells such as oligodendroglia, microglia, and astrocytes generally were not endothelin-converting enzyme-immunoreactive, although astrocytes were rarely stained. Endothelin-converting enzyme-, endothelin-1-, and endothelin-3-like immunoreactivities were generally found co-existing in given nuclei. The diversity of neurons immunostained for endothelin suggests multiple roles of endothelin in the CNS.

Animals↗
PubMed1999

The role of endothelin in mediating virus-induced changes in endothelinB receptor density in mouse airways.

Emerging evidence supports a mediator role for endothelin (ET)-1 in airway diseases including asthma. Respiratory tract viral infections, are associated with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are causally linked, perhaps involving ET-1-induced ET(B) receptor downregulation, the current study investigated the influence of in vivo administration of CGS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET-content and ET(B) receptor density. CGS 26303 (5 mg x kg(-1) x day(-1)) or placebo was administered to mice via osmotic minipumps implanted subcutaneously. Two days after implantation, mice were inoculated with influenza A/PR-8/34 virus or sham-infected, and all measurements were performed on tissue obtained on the fourth day post-inoculation. Viral infection was associated with elevated levels of immunoreactive ET and decreased densities of ET(B) receptors in murine airways. Both of these effects were attenuated in virus-infected mice that had received CGS 26303. Virus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of infectious virus in the lungs and similarly, viral infection had no effect on the plasma levels of free CGS 26303. In summary, CGS 26303 inhibited the virus-induced changes in both immunoreactive endothelin content and endothelinB receptor density. These findings are consistent with the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelinB receptors in airway smooth muscle. Whether inhibitors of endothelin synthesis attenuate virus-induced exacerbations of asthma or airways hyperresponsiveness remains to be established.

Animals↗
PubMed1998

Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.

Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.

Acetylene↗
PubMed1998

Sulfonamide-based hydroxamic acids as potent inhibitors of mouse macrophage metalloelastase.

The structural requirements of sulfonamide-based hydroxamic acid 1 for inhibition of macrophage metalloelastase (MME) were investigated. A short aliphatic group at the R2 position together with an aromatic group at the R3 position significantly improved the inhibitory activity. Compounds 32, 34, and 40 were the most potent inhibitors of MME with IC50 values between 5 and 6 nM.

Animals↗
PubMed1998

Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells.

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.

Animals↗
PubMed1998

Differential inhibition of wild-type endothelin-converting enzyme-1 and its mutants.

The purpose of this study was to determine the effect of mutation of rat endothelin-converting enzyme-1 (ECE-1) on the potencies of various inhibitors. The two amino acids mutated were Cys(412), which was shown to link the two monomeric enzymes to form a dimer, and Glu(752), postulated to be involved in substrate and inhibitor binding. No significant effects were noted when Glu(752) was replaced by an acidic (E752D) or uncharged (E752Q) residue. Replacing Glu(752) by a basic residue (E752R) slightly weakened the potencies of the inhibitors. In contrast, a significant decrease in the potencies was observed with the monomeric enzyme C412S. Phosphoramidon inhibited the wild-type ECE-1 with an IC50 of 1.5 microM, but it was about sixfold weaker for the C412S mutant. CGS 31447, an aminophosphonic acid, inhibited the wild-type and C412S enzymes with IC50 values of 5.8 and 76 nM, respectively. A similar degree of change in the potencies was also seen with CGS 25015, a thiol-containing compound, which inhibited the respective enzymes with IC50 values of 17 and 190 microM. These results suggest that the charge in Glu(752) may not be important for inhibitor binding and that the dimeric ECE-1 is more susceptible to inhibition than the monomeric enzyme.

Animals↗
PubMed1998

Characterization of CGS 31447, a potent and nonpeptidic endothelin-converting enzyme inhibitor.

Optimization of an aminophosphonic acid series of compounds for inhibition of endothelin-converting enzyme (ECE) has led to the discovery of CGS 31447. This compound reversibly inhibited the activity of recombinant human ECE-1 with an IC50 value of 21 nM. The effect of CGS 31447 was not due to nonspecific chelation of the zinc ion at the catalytic center of ECE-1 by the phosphonic acid of the inhibitor. Determination of kinetic parameters of ECE-1 in the presence of 5-15 nM CGS 31447 revealed the competitive nature of the compound; a K1 of 7 nM was obtained. CGS 31447 infused at concentrations of 0.01, 0.1, and 1.0 microM inhibited the mean increase in big ET-1-induced pressor responses in isolated and perfused rat kidneys by 7, 39, and 68%, respectively, compared with the controls. These results demonstrate that CGS 31447 is a potent, reversible, and competitive inhibitor of ECE-1.

Animals↗
PubMed1998

Benzofused macrocyclic lactams as triple inhibitors of endothelin-converting enzyme, neutral endopeptidase 24.11, and angiotensin-converting enzyme.

The purpose of this study was to identify endothelin-converting enzyme (ECE) inhibitors that also possess inhibitory activity for neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE). The ortho-substituted benzofused macrocyclic lactams, such as CGS 26670, are generally potent NEP inhibitors but poor ACE inhibitors. CGS 26670 inhibited ECE activity with an IC50 of 600 nM, whereas it inhibited NEP and ACE activities with IC50 values of 0.9 and > 10,000 nM, respectively. This compound also prevented the conversion of big endothelin-1 (big ET-1) to ET-1 by denuded porcine coronary arterial smooth muscle with an IC50 of 200 nM. The ACE inhibitory activity is greatly is greatly improved in metasubstituted benzofused macrocyclic lactams. For example, CGS 26582 inhibited ECE, NEP, and ACE activities with IC50 values of 620, 4, and 175 nM, respectively. When injected at 30 mg/kg i.v. in conscious rats, followed by a challenge with big ET-1 at 1 nmol/kg i.v., this compound suppressed by 44% the increase in mean arterial blood pressure owing to the generation of ET-1 by ECE. Because ECE, NEP, and ACE play regulatory roles in cardiovascular and renal function, triple inhibitors of these enzymes may represent a novel class of agents for treatment of cardiovascular and renal diseases.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Attenuation of experimental subarachnoid hemorrhage-induced cerebral vasospasm by CGS 26303, an endothelin-converting enzyme inhibitor.

The effect of CGS 26303, an endothelin-converting enzyme inhibitor, on the prevention and reversal of cerebral vasospasm was investigated in a rabbit model of subarachnoid hemorrhage (SAH). In the prevention study, rabbits were injected with 3 ml of autologous blood in the cisterna magna and treatment with CGS 26303 i.v. was initiated 1 h later. The compound was subsequently administered at 12, 24, and 36 h post SAH and animals were sacrificed at 48 h post SAH. Treatment with CGS 26303 at 3, 10, and 30 mg/kg resulted in dose-dependent increases in the concentrations of the compound in cerebrospinal fluid samples, and the arterial narrowing after SAH was significantly attenuated in all three groups. Morphologically, corrugation of the internal elastic lamina of vessels was often observed in the vehicle-treated group, but it was not prominent in the CGS 26303-treated groups and the healthy controls. In the reversal study, treatment with CGS 26303 was initiated 24 h post SAH and a second injection was given 12 h later. Arterial narrowing was significantly attenuated in rabbits treated with CGS 26303 at 30 mg/kg. These results demonstrate that CGS 26303 may be an effective agent in prevention and reversal of cerebral vasospasm after aneurysmal SAH.

Animals↗
PubMed1997

Suppression of substance P biosynthesis in sensory neurons of dorsal root ganglion by prodrug esters of potent peptidylglycine alpha-amidating monooxygenase inhibitors.

Substance P as well as many other neuropeptides are synthesized as glycine-extended precursors and converted to the biologically active C-terminal amides by posttranslational modification. The final step of posttranslational processing is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM). In a previous study, N-substituted homocysteine analogs were found to be potent inhibitors of PAM partially purified from conditioned medium of cultured rat medullary thyroid carcinoma CA-77 cells. These compounds, however, were only modest inhibitors of substance P production in cultured dorsal root ganglion cells, possibly because of poor cell penetration. Several ester derivatives of hydrocinnamoyl-phenylalanyl-homocysteine, one of the most potent PAM inhibitors, were prepared to increase the intracellular accessibility of these compounds. Hydrocinnamoyl-phenylalanyl-(S-benzoyl-homocysteine) benzyl ester was identified as the most potent compound, inhibiting substance P biosynthesis in dorsal root ganglion cells with an IC50 of 2 microM. Inhibition of PAM resulted in a concomitant increase in the glycine-extended substance p (substance P-Gly) precursor peptide. In the presence of 3 microM benzyl ester derivative, the intracellular substance P-Gly level was 2.4-fold higher while the substance P level was 2.1-fold lower than the corresponding peptides in control cells. These results suggest that PAM inhibition represents an effective method for suppression of substance P biosynthesis and, therefore, may have therapeutic utility in conditions associated with elevated substance P levels. Furthermore, PAM inhibition may also prove useful in decreasing other amidated peptides.

Animals↗
PubMed1997

Activation of BK(Ca) channel via endothelin ET(A) receptors in porcine coronary artery smooth muscle cells.

It has been demonstrated previously that endothelin-1 stimulates the Ca2+-activated K+ (BK(Ca)) channel activity in porcine coronary artery smooth muscle cells. The purpose of the present study was to delineate the endothelin receptor subtype involved in this action. In receptor binding studies, [125I]endothelin-1 was shown to bind to the homogenate of porcine primary coronary artery smooth muscle cells in a single class of binding sites with K(D) and Bmax values of 73 pM and 99 fmol/mg protein, respectively. Furthermore, endothelin-1 and endothelin-3 displaced the binding of [125I]endothelin-1 to these cells with respective IC50 values of 70 and 17000 pM, a 240-fold difference in potency. The effects of endothelin-3 on the activity of the BK(Ca) channel in porcine coronary artery smooth muscle cells were examined using the cell-attached patch-clamp technique. Similar to endothelin-1, endothelin-3 also exhibited a bell-shaped concentration-response curve. A maximal increase of 95% in channel open-state probability (Po) was induced by 100 nM endothelin-3 as compared with the 320% increase in Po by 1 nM endothelin-1. Thus, endothelin-1 was about 100-fold more potent and 3.4-fold more efficacious than endothelin-3 in this action. Both the receptor binding and the electrophysiological results suggest that the effects of endothelins on the BK(Ca) channel are mediated through the endothelin ET(A) receptor subtype.

Animals↗
PubMed1997

Modulation of endothelin production and metabolism in guinea-pig tracheal epithelial cells by peptidase inhibitors.

Endothelins (ET-1, ET-2, ET-3) are potent bronchoconstrictors and growth-promoting mediators. They are released from various cells such as endothelial and epithelial cells. In the airways, ETs are released under basal and stimulated conditions. In patients with status asthmaticus and other pulmonary disorders, the expression and production of ET-1 are increased. We investigated the activities of endothelin-converting enzymes (ECE) and endothelin-degrading enzymes, mostly neutral endopeptidases (NEP), in guinea-pig tracheal epithelial cells in culture through the use of various enzyme inhibitors. We found that among ETs, only ET-1 was steadily released under basal conditions over 24 h. The basal production was attenuated by both phosphoramidon and CGS 26 303, dual NEP and ECE inhibitors. Conversely, thiorphan, a selective NEP inhibitor, did not attenuate but rather increased the concentration of ET-1 in cell supernatants. CGS 24 592 and SQ 28 603, other NEP inhibitors, also increased the concentrations of ET-1 in cell supernatants in a concentration-dependent manner. However, at a high concentration, SQ 28 603 also inhibited the basal release of ET-1, which would suggest a non-selective inhibitory activity against ECE. These data suggest that ET-1 is simultaneously produced and degraded by guinea-pig tracheal epithelial cells via phosphoramidon-sensitive ECE and NEP pathways, respectively. This observation is of interest when considering that asthmatic patients were shown to have a damaged airway epithelium combined with the loss of NEP activity, which was associated with an increased expression and production of ET-1.

Animals↗
PubMed1997

Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage.

Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

Animals↗
PubMed1996

Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.

Angiotensin-Converting Enzyme Inhibitors↗