Omapatrilat was originally identified as a selective dual inhibitor of angiotensin-converting enzyme (ACE) and neprilysin (NEP). The K values of omapatrilat against NEP, NEP2, endothelin-converting enzyme 1 (ECE1), ACE, and aminopeptidase P (APP) were 0.00045, 0.025, 10, 0.00064, and 0.25μM, respectively. In Sprague–Dawley rats subjected to an optimal dose of bradykinin (100ng/min), omapatrilat (0.0, 0.53, 1.76, or 5.3mg/kg) resulted in a dose-dependent reduction in the mean arterial blood pressure area under the curve (MAP AUC). Peak reduction was observed in the group administered with 1.76 and 5.3mg/kg omapatrilat. The effect of omapatrilat on MAP AUC was reduced when the doses of bradykinin decreased (10 and 30ng/min). Rats administered with omapatrilat at doses of 1.76 and 5.3mg/kg exhibited blunted reflex tachycardia.[1]
作用机制
Omapatrilat exhibits potent inhibitory activity against three bradykinin-metabolizing enzymes: NEP, ACE, and APP. The concomitant inhibition of both APP and ACE by omapatrilat is probably the primary mechanism responsible for the large depressor response in rats and angioedema in patients.[1]
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