The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Seed, Alison; Kuc, Rhoda E.; Maguire, Janet J.; Hillier, Chris; Johnston, Fiona; Essers, Hans; Voogd, Hanka J. de; McMurray, John J.V.; Davenport, Anthony P.

doi:10.1016/j.lfs.2012.03.022

Cited by 28 publications

(27 citation statements)

References 53 publications

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“…by guest on http://circres.ahajournals.org/ Downloaded from BP and proteinuria and prevent nephrosclerosis as effectively as the ACE inhibitor captopril. 90,94 Daglutril has also been shown to be safe and well tolerated in healthy volunteers, 92,95 and biomarker measurements confirmed dual suppression of neprilysin and endothelin-converting enzyme activity in these subjects. 92 Data from a multicenter, randomized controlled trial performed in 75 patients with HF showed that daglutril reduced pulmonary and right atrial pressures without affecting systemic arterial pressure, cardiac output, or heart rate.…”

Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 86%

“…90,94 Daglutril has also been shown to be safe and well tolerated in healthy volunteers, 92,95 and biomarker measurements confirmed dual suppression of neprilysin and endothelin-converting enzyme activity in these subjects. 92 Data from a multicenter, randomized controlled trial performed in 75 patients with HF showed that daglutril reduced pulmonary and right atrial pressures without affecting systemic arterial pressure, cardiac output, or heart rate. 89 Daglutril has also been shown in a small randomized, doubleblind, placebo-controlled crossover trial to lower BP but not to reduce albuminuria in patients with type 2 diabetes mellitus and nephropathy.…”

Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 86%

“…Orally active dual inhibitors of neprilysin and endothelinconverting enzyme have been developed, and one of these (daglutril, SLV-306) has been studied in rodent models of diabetes mellitus and in patients with hypertension, HF, and type 2 diabetes mellitus [89][90][91][92][93] (Figure 4; Table). Daglutril is a prodrug that is hydrolyzed after oral administration to the active metabolite KC-12615, a mixed inhibitor of neprilysin and endothelin-converting enzyme.…”

Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 99%

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New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

243

137

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 86%

Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 86%

Section: Dual-acting Endothelin Converting Enzymeneprilysin Inhibitorsmentioning

confidence: 99%

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New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

243

137

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“…Changes of hemodynamics are more difficult to cope for elderly patients, who also experience a gradual decline of GFR by 1% per year starting at age 45. Novel pharmacological approaches to block either binding or formation of ET by inhibiting ET converting enzymes (Nelissen et al, 2012;Seed et al, 2012), or by combining ERAs with drugs targeting other G protein-coupled receptors (Kowala et al, 2004;Kurtz and Klein, 2009;Mohanan et al, 2011;Murugesan et al, 2005;Neutel et al, 2008), may prove effective to block the ET pathway in disease.…”

Section: Current Perspectives For Era Therapy In Clinical Medicinementioning

confidence: 99%

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

et al. 2012

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In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

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“…An orally active ECE/NEP inhibitor (SLV-306 or daglutril) caused a concentration dependent attenuation of the hypertensive response to big ET-1 infusion, a parallel increase of plasma ANP levels, without changes in plasma ET-1 concentration, in healthy volunteers, suggesting that the biological active peptide can be removed from the circulation by ET B clearance receptors [99]. ECE/NEP blockade has so far revealed important protective effects on cardiac remodeling in a rat model of renovascular hypertension [100], on improvement of cardiac function and of cardiac remodeling following myocardial infarction [101].…”

Section: Atrial Natriuretic Peptide-based Therapeutic Approachesmentioning

confidence: 99%

Atrial natriuretic peptide and regulation of vascular function in hypertension and heart failure

Rubattu¹,

Calvieri²,

Pagliaro³

et al. 2013

Journal of Hypertension

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Atrial natriuretic peptide (ANP) plays a pivotal role in modulation of vascular function and it is also involved in the pathophysiology of several cardiovascular diseases. We provide an updated overview of the current appraisal of ANP vascular effects in both animal models and humans. We describe the physiological implications of ANP vasomodulatory properties as well as the involvement of ANP, through its control of vascular function, in hypertension and heart failure. The principal molecular mechanisms underlying regulation of vascular tone, that is natriuretic peptide receptor type A/cyclic guanylate monophosphate, natriuretic peptide receptor type C, nitric oxide system, are discussed. We review the literature on therapeutic implications of ANP in hypertension and heart failure, examining the potential use of ANP analogues, neutral endopeptidase (NEP) inhibitors, ACE/NEP inhibitors, angiotensin receptor blocker (ARB)/NEP inhibitors, the new dual endothelin-converting enzyme (ECE)/NEP inhibitors and ANP-based gene therapy. The data discussed support the role of ANP in different pathological conditions through its vasomodulatory properties. They also indicate that ANP may represent an optimal therapeutic agent in cardiovascular diseases.

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The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Abstract: SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease.

Cited by 28 publications

References 53 publications

New Approaches in the Treatment of Hypertension

New Approaches in the Treatment of Hypertension

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

Atrial natriuretic peptide and regulation of vascular function in hypertension and heart failure

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