Vasopeptidase inhibition is a new concept in cardiovascular
therapy. It involves simultaneous inhibition with a single molecule of two key
enzymes involved in the regulation of cardiovascular function,
neutral endopeptidase (EC 24.11; NEP) and
angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory
peptides (including
atrial natriuretic peptide [
ANP],
brain natriuretic peptide [BNP] of myocardial cell origin, and
C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other
vasodilator peptides including
bradykinin and
adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the
natriuretic peptide system,
vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure.
Omapatrilat, a heterocyclic
dipeptide mimetic, is a novel
vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike
ACE inhibitors,
omapatrilat demonstrates
antihypertensive efficacy in low-, normal-, and high-
renin animal models. Unlike NEP inhibitors,
omapatrilat provides a potent and sustained
antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human
essential hypertension. In animal models of
heart failure,
omapatrilat is more effective than ACE inhibition in improving cardiac performance and
ventricular remodeling and prolonging survival.
Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models.
Omapatrilat is the first VPI to enter advanced USA clinical trials.
Omapatrilat appears to be a safe, well-tolerated and effective
antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including
hypertension and
heart failure, that may offer advantages over currently available
therapies.