Vasopeptidase Inhibitors
Overview
Vasopeptidase inhibitors are a novel class of agents that inhibit the zinc-containing metallopeptidases, angiotensin-converting enzyme (angiotensin-converting enzyme) and neutral endopeptidase (NEP). Vasopeptidase inhibitors have been in late-stage clinical development for the management of hypertension and chronic heart failure for several years. The FDA’s refusal to license the lead compound in this class (omapatrilat [Bristol-Myers Squibb's Vanlev]) for hypertension has greatly tempered initial enthusiasm for these compounds, which were previously considered potential blockbusters. The FDA will probably require significant evidence of this class’s safety and superiority over established agents before it grants approval for hypertension.
The diminished enthusiasm for this class has led to the discontinuation of research into the antihypertensive effects of at least two compounds that were in the later stages of clinical trials, Shire’s sampatrilat and gemopatrilat (also being developed by Bristol-Myers Squibb). Aventis has also discontinued development of its dual angiotensin-converting enzyme/NEP inhibitor M-100240 for hypertension after disappointing Phase II results.
Some Vasopeptidase inhibitors are still in development. Aventis’s AVE-7688 is in early-stage clinical development for hypertension and diabetic neuropathy in Europe. In Italy, the Zambon Group’s GW-660511 is in Phase I clinical trials for hypertension. GlaxoSmithKline was previously developing this compound but terminated its involvement in October 2002.
Mechanism Of Action
Vasopeptidase inhibitors inhibit the action of the zinc-containing metallopeptidases angiotensin-converting enzyme and NEP. angiotensin-converting enzyme inhibition prevents some All-mediated vasoconstriction; NEP inhibition facilitates the actions of the vasodilatory natriuretic pep tides and kinins.
Blocking the production of All — and subsequently, aldosterone — increases cardiac output and reduces sodium and water retention. All is also known to stimulate contraction of the vascular smooth-muscle cells lining the vascular wall, an action ultimately leading to hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number). This action manifests as a thickening of the arterial wall and a narrowing of the lumen, developments that increase the peripheral resistance of the vasculature. All also increases production of excess reactive oxygen species (ROS), which in turn increases vasoconstriction and damages the endothelial wall.
Blocking the action of NEP increases the half-life of bradykinin, atrial natriuretic peptide (atrial natriuretic peptide), and B-type natriuretic peptide (brain natriuretic peptide). Bradykinin acting through angiotensin-converting enzyme-bradykinin type 2 (B2) receptors is known to mediate cardiopro-tective effects (an effect previously observed in ACEIs). Both atrial natriuretic peptide and brain natriuretic peptide increase sodium and water excretion by the kidney, relax vascular smooth muscle (except arterioles of the renal glomeruli, which vasoconstrict in response to these agents), increase vascular permeability, and inhibit the release of or actions of various humoral factors, including aldosterone, endofhelin-1 (ET-1), All, and arginine vasopressin (AVP).
Omapatrilat
Fasidotril
Fasidotril is a dual vasopeptidase inhibitor under development by Eli Lilly (licensed from Bioproject). A pro-drug of the active metabolite fasidoprilat, it is a mixed inhibitor of angiotensin-converting enzyme and neutral endopeptidase. Phase II clinical trials are ongoing in France. The company expects to file an NDA in Europe in 2006. In animal models, fasidotril treatment (100 mg/kg orally, twice daily for three weeks) resulted in a progressive and sustained decline in systolic blood pressure ( — 20 to — 30 mm Hg). Clinical data on this agent are scarce, but in a randomized, double-blind, placebo-controlled, parallel-group study, 57 patients with essential hypertension (hypertension without comorbidities) received fasidotril (100 mg twice daily) or placebo for six weeks. After 42 days, fasidotril reduced supine systolic blood pressure and diastolic blood pressure by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg, compared with placebo.
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