Vasopeptidase Inhibitors

Vasopeptidase inhibitors are drugs that are capable of simultaneously inhibiting ACE and the neutral endopeptidase (NEP, also known as EC 24.11). NEP is a cell surface metalloprotease that degrades various bioactive peptides, including big endothelin-1. Inhibition of NEP is anticipated to reduce the formation of endothelin-1 from big endothelin-1. None of the vasopeptidase inhibitors are currently marketed in the US. The first dual inhibitors, thiazepinones and oxazepinones, were synthesized at Bristol-Myers Squibb. In 1998 Trippodo et al. described the antihypertensive activity of the lead compound from this series, omapatrilat (see Figure 4).43 Omapatrilat lowered arterial pressure in normal and high renin models of hypertension, prevented vascular remodeling, and provided long-term renoprotection to rats. In the initial clinical studies omapatrilat appeared to be highly promising, but a subsequent large clinical trial found that the rate of angioedema with omapatrilat was three times higher than that with enalapril.44 Angioedema is considered to be a class effect and is likely to prevent further development of vasopeptidase inhibitors, unless drugs with substantially lower incidence of angioedema are discovered or the high-risk population for this side effect is better defined.

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