Neutral Endopeptidase Inhibitors
Overview
The natriuretic peptides are endogenously released molecules that counteract the effects of the renin-angiotensin-aldosterone system. They lower blood pressure by triggering vasodilation and increasing diuresis.
Natriuretic peptides are released by the atria and ventricles of the heart in response to the stretching of the myocardium from the fluid overload characteristic of heart failure. Natriuretic peptides are rapidly cleared (the half-life of atrial natriuretic peptide is two to five minutes) as a result of the breakdown by neutral endopeptidases (NEPs) on cell membranes. Their short half-life severely limits their therapeutic potential in chronic conditions such as hypertension. As a result, research has focused on inhibiting NEPs, thereby increasing endogenous levels of natriuretic peptides. Other beneficial effects of NEP inhibition include a reduction in the formation of the active form of ET-1 and an increase in the availability of the potent vasodilator peptide adrenomedullin (also a substrate for NEP).
Mechanism Of Action
The natriuretic peptides atrial natriuretic peptide and brain natriuretic peptide are released from the atria and ventricles, respectively, in response to mechanical stretching of the heart wall due to fluid overload. Natriuretic peptides can also be released in response to ET-1, arginine vasopressin, and catecholamines. NEPs (namely endopeptidase 24.11) on the microvillar membranes of the kidney target and degrade these vasodilatory natriuretic peptides and kinins, preventing their antihypertensive action. NEP inhibition prevents this degrading action and facilitates the vasodilatory effects of atrial natriuretic peptide, brain natriuretic peptide, and kinins such as bradykinin.
Ecadotril
Originally licensed to Shionogi and Bayer, ecadotril (Sinorphan) is under development by Bioproject, a privately owned drug research company, for the treatment of hypertension and chronic heart failure. The molecule is in Phase III trials in Europe. Phase II trials were carried out in Japan and Germany, but Shionogi and Bayer subsequently discontinued development of ecadotril in these countries.
Ecadotril is an orally active inhibitor of NEP 24.11, a constitutively expressed NEP responsible for the catabolysis of atrial natriuretic peptide and brain natriuretic peptide. Ecadotril has been shown to compete with NEP 24.11 for binding sites in the kidney (a major site for NEP activity) and protect against atrial natriuretic factor (atrial natriuretic peptide) degradation.
Initial results from studies using animal models have shown that ecadotril inhibits the development of aggressive hypertension and cardiac hypertrophy in young rats and improves cardiac function and reduces cardiac hypertrophy in older rats with compromised cardiac function. However, another study in a rat myocardial infarction (MI) model yielded antihypertrophic effects only when ecadotril was given in combination with the ACEI perindopril. Such studies raise questions about the compound’s efficacy.
Phase II trial data in 12 moderately hypertensive patients showed ecadotril (100 mg twice daily) reduced systolic blood pressure and diastolic blood pressure after 42 days, with no serious side effects and no effects on heart rate. In a double-blind, crossover study, 16 hypertensive patients were treated with ecadotril (100 mg twice daily) or captopril (25 mg twice daily). At the end of the treatment period, the medications were combined for a further four weeks. A significant reduction of systolic blood pressure and diastolic blood pressure was observed when the two agents were coadministered. However, after four weeks of treatment with ecadotril alone or in combination with captopril, no change in plasma atrial natriuretic peptide level was observed.
The lack of effect on atrial natriuretic peptide levels contradicts earlier findings in 12 patients with severe chronic heart failure; a single dose of ecadotril (10 mg, 20 mg, or 40 mg) increased atrial natriuretic peptide levels by approximately 80-100% above the control level (which was already increased by approximately 15-fold, compared with healthy persons) in a non-dose-dependent manner. This action was accompanied by reductions in diastolic blood pressure.
However, in a placebo-controlled, dose-ranging study, 279 patients with chronic heart failure were treated with ecadotril (50 mg, 100 mg, 200 mg, and 400 mg). Patients did not show symptomatic benefit or significant improvement in quality-of-life score. Moreover, seven deaths occurred in the ecadotril group, while no deaths were noted in the placebo group of 56 patients. Ecadotril was well tolerated at low doses but at high doses was found to induce idiosyncratic aplastic anemia. Such anemia can often be irreversible.
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