CGS 24128: A Long‐Acting Inhibitor of Neutral Endopeptidase 3.4.24.11

Trapani, Angelo J.; Smits, J. F. M.; Sun, Xinyuanyuan; Webb, Randy L.; Yau, E. T.

doi:10.1111/j.1527-3466.1994.tb00294.x

Cited by 5 publications

(2 citation statements)

References 56 publications

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“…Clearly the combination of ACE inhibitor with NEP inhibitory activity provided better renal protection than an equal dose of a selective ACE inhibitor. These results are consistent with experimental data demonstrating significant additive or synergistic effects of an ACE inhibitor and a NEP inhibitor in experimental models of congestive heart failure and hypertension (40,51,61,62,67,68). Elucidation of the specific mechanism(s) underlying these effects though still remains to be resolved.…”

Section: Reduced Renal Masssupporting

confidence: 90%

“…As a consequence of these observations, it was hypothesized that blockade of the renin-angiotensin system with an ACE inhibitor coupled with the potentiation of ANP through NEP inhibition would provide therapeutic efficacy greater than that produced by inhibition of either enzyme alone. Combination therapy of a selective ACE inhibitor and a selective NEP inhibitor or treatment with single molecules containing both activities have confirmed this hypothesis by demonstrating additive or synergistic benefits in animal models of hypertension, CHF and chronic renal failure (14,40,51,61,62,(67)(68)(69). Moreover, simultaneous administration of the ACE inhibitor captopril with sinorphan, a NEP inhibitor, to patients with essential hypertension conferred synergistic antihypertensive effects (21).…”

Section: Introductionmentioning

confidence: 89%

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CGS 30440: A Dual Inhibitor of Angiotensin‐Converting Enzyme and Neutral Endopeptidase 24.11

Cohen

Fink

Trapani

et al. 1999

Cardiovascular Drug Reviews

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Section: Reduced Renal Masssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 89%

CGS 30440: A Dual Inhibitor of Angiotensin‐Converting Enzyme and Neutral Endopeptidase 24.11

Cohen

Fink

Trapani

et al. 1999

Cardiovascular Drug Reviews

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Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats

Webb

Navarrete

Davis

et al. 1998

Journal of Hypertension

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These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

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Effects of the Novel Dual Inhibitor of Neutral Endopeptidase and Angiotensin-Converting Enzyme, CGS 30440, on Blood Pressure and Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Webb

Abramson²,

Beil³

et al. 1997

Journal of Cardiovascular Pharmacology

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This study examined the long-term effects of CGS 30440 on blood pressure, heart rate, cardiac hypertrophy, and urinary parameters in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in mean arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 producing a maximal sustained response of 40 mm Hg. CGS 30440 significantly inhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) were inhibited by >60 and >90%, respectively. Urinary cyclic guanosine monophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose of an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respectively. Heart-rate responses were not different between treatment groups. Left ventricular hypertrophy (LV weight/body weight ratio) was reduced significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.26 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats receiving only vehicle. These results demonstrate that CGS 30440 is a potent, orally active antihypertensive agent with a long duration of action. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, has been shown to be a novel antihypertensive agent with dual ACE/NEP inhibitory activity in SHRs.

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CGS 24128: A Long‐Acting Inhibitor of Neutral Endopeptidase 3.4.24.11

Cited by 5 publications

References 56 publications

CGS 30440: A Dual Inhibitor of Angiotensin‐Converting Enzyme and Neutral Endopeptidase 24.11

CGS 30440: A Dual Inhibitor of Angiotensin‐Converting Enzyme and Neutral Endopeptidase 24.11

Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats

Effects of the Novel Dual Inhibitor of Neutral Endopeptidase and Angiotensin-Converting Enzyme, CGS 30440, on Blood Pressure and Cardiac Hypertrophy in Spontaneously Hypertensive Rats

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