Dual Neutral Endopeptidase/Endothelin-Converting Enzyme Inhibitors
Overview
Natriuretic peptides are intimately involved in the control and regulation of blood pressure and plasma volume in the body and are degraded by endogenous NEPs (as described in the previous section, “Neutral Endopeptidase Inhibitors”). In humans, increasing levels of atrial natriuretic peptide and brain natriuretic peptide reduce blood pressure by causing vasodilation and increasing diuresis. Conversely, the family of peptides known as the endothelins possesses potent vasoconstrictor activity. Endothelin-1 (ET-1) is the most physiologically potent of the endothelins, and evidence suggests that it has a pathogenic role in cardiovascular disorders, including hypertension, as well as contributing to left-ventricular remodeling and progression of heart failure.
A group of antihypertensive drugs is in development that modulates the endogenous levels of both natriuretic peptides and ETs in a beneficial way (i.e., simultaneously modulating levels of natriuretic peptides up and ETs down). Drugs in this class have diuretic and vasodilatory properties, and researchers hope the dual mechanism of action will give these molecules a significant advantage over currently available agents.
Mechanism Of Action
ET-1 is formed by the cleavage of the endothelin precursor, big endothelin (big-ET), by endothelin-converting enzyme (ECE). Hence, inhibition of ECE leads to a reduction of physiologically active ET-1 and the associated vasoconstricting activity of this molecule.
Natriuretic peptides are released in response to various stimuli, such as the mechanical stretching of the heart wall due to fluid overload, arginine vasopressin, and catecholamines. NEPs target and degrade these vasodilatory natriuretic peptides, preventing their antihypertensive action. NEP inhibition prevents this degrading action and facilitates the vasodilatory effects of natriuretic peptides.
Both ECE and NEP belong to a class of molecules called the metalloproteases and share significant sequence homology. Agents in the dual NEP/ECE inhibitor class competitively inhibit both NEP and ECE. By increasing circulating levels of natriuretic peptides and reducing levels of ET-1, ECE/NEP inhibitors increase the vasodilatory/natriuretic properties of the former molecules while reducing vasoconstriction caused by the latter.
SLV-306
SLV-306 (also known as Dalutril, KC-12792), an orally active NEP/ ECE inhibitor being developed by Solvay, is in Phase II trials for hypertension and heart failure in Europe. SLV-306 competitively inhibits a newly discovered ECE target, human soluble endopeptidase (hSEP), for which Solvay has filed a patent.
In animal models, SLV-306 (10 mg/kg, IV) showed antihypertensive activity in hypertensive rats and dose-dependently increased diuresis and natriuresis after oral administration in conscious saline-loaded rats. After oral administration, SLV-306 is metabolized to its active form, KC-12615, which has also demonstrated antihypertensive activity in animal models.
In a Phase I study, 13 healthy volunteers were randomized to placebo or one of three dose regimens of SLV-306 to obtain average plasma concentrations of KC-2615 of 75ng/mL, 300 ng/mL, and l,200 ng/mL. This step was followed by infusions of 8 pmol/kg and 12 pmol/kg of big-ET. Following the second dose of big-ET, significant reductions in systolic blood pressure and diastolic blood pressure and endothelin-1 were observed in the SLV-306 group versus the placebo group, accompanied by an increase in natriuretic peptide and big-ET. Solvay also reported that SLV-306 significantly reduced both diastolic blood pressure and systolic blood pressure in a Phase II clinical study in patients with essential hypertension.
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