Heart Endopeptidase

AHF acute heart failure, CHF chronic heart failure, CRF chronic renal failure, NEP neutral endopeptidase, ECE endothelin converting enzyme, PAH pulmonary arterial hypertension. 

A series of bi- and tricyclic pyridoazepine-type lactams was studied as conformationally restrained peptide mimetics acting as ACE inhibitors or dual inhibitors, that is both ACE and neutral endopeptidase (NEP) inhibitors, especially by the groups of Flynn and Robl. ACE and NEP are zinc metalloproteases acting as vasopeptidases. The respective inhibitors are used in the treatment of hypertension, congestive heart failure, and other cardiovascular diseases. 

In addition, a new class of drugs, termed vasopepti-dase inhibitors, inhibit the enzymatic activity of ACE and neutral endopeptidase, the enzyme responsible for the breakdown of natriuretic peptides. The end result is a reduction in the synthesis of angiotensin II and an increase in the circulating level of natriuretic peptides such as ANP. Omapatrilat, a vasopeptidase inhibitor, is under study for the treatment of hypertension and congestive heart failure. 

Excreted primarily in the heart by the left ventricle. Metabolized by the natriuretic neutral endopeptidase enzymes on the vascular luminal surface. Half-life 18-23 min. 

Administration of BNP as nesiritide (see Chapter 13 Drugs Used in Heart Failure) in patients with severe heart failure increases sodium excretion and improves hemodynamics. However, the peptide has to be given by constant intravenous infusion. A more promising approach may be the use of drugs that inhibit the neutral endopeptidase responsible for the breakdown of ANP. This is discussed below under Vasopeptidase Inhibitors. 

Of these, omapatrilat is at the most advanced stage of clinical development. It lowers blood pressure in animal models of hypertension as well as in hypertensive patients and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema in addition to cough and dizziness. Nevertheless, combined inhibition of neutral endopeptidase NEP 24.11 and ACE with this new class of drugs may be a promising approach to treat cardiovascular disease and further clinical trials are underway. 

ANP is a polypeptide hormone that is secreted in large quantities by the atrial portion of the heart and from a variety of other mammalian cell types. It exerts many of its actions via activation of particulate guanylate cyclase [16, 134]. ANP is present in human follicular fluids [163] and specific ANP receptors have been identified in human spermatozoa [144]. Sperm chemotaxis to ANP was demonstrated by sperm accumulation in capillaries with ascending [6] and descending [192] gradients and by choice assays [192] (Table 4). It is not yet known whether ANP is involved in sperm chemotaxis in vivo and whether the physiological chemoattractant for human spermatozoa is an ANP-like substance. Since chemotaxis to ANP at physiological concentrations can be observed only in the presence of a neutral endopeptidase inhibitor such... 

In a recent example, linear selective hydroformylation was employed in a large-scale synthesis of (5)-allysine ethylene acetal, reported by Chirotech. (5)-Allysine ethylene acetal is a key intermediate for several angiotensin-I converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors (for example, omapatrilat) that are currently in chnical trials (Scheme 14.3.). The inhibition of both these (ACE and NEP) enzymes by a single drug is an approach used for the treatment of cardiovascular diseases such as hypertension and heart failure. The product produced in Scheme 14.3 is also a possible precursor for (3-lactam antibiotics. ... 

Eisner D, Muntze A, Kromer EP, Riegger GAJ. Effectiveness of endopeptidase inhibition (Candoxantril) in congestive heart failure. Am. J. Cardiol. 1992 70(4) 494—498. 

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