Omapatrilat is an orally bioavailable angiotensin-converting enzyme (ACE) and neprilysin (NEP) inhibitior (IC50s = 1.7 and 5.3 nM, respectively, for the human enzymes).1 It inhibits the pressor response induced by angiotensin I in normotensive rats (ED50 = 0.07 ?mol/kg) and lowers mean arterial pressure (MAP) in sodium-depleted spontaneously hypertensive rats when administered at a dose of 30 ?mol/kg.2 Omapatrilat lowers MAP in rats when co-administered with bradykinin .3 It also increases tracheal plasma extravasation in a rat model of upper airway angioedema in a dose-dependent manner.4
1.Sulpizio, A.C., Pullen, M.A., Edwards, R.M., et al.Mechanism of vasopeptidase inhibitor-induced plasma extravasation: Comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-converting enzyme inhibitor GW796406J. Pharmacol. Exp. Ther.315(3)1306-1313(2005) 2.Robl, J.A., Sun, C.-Q., Stevenson, J., et al.Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidaseJ. Med. Chem.40(11)1570-1577(1997) 3.Fryer, R.M., Segreti, J., Banfor, P.N., et al.Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: Rank efficacy of enzymes associated with bradykinin-mediated angioedemaBr. J. Pharmacol.153(5)947-955(2008) 4.Murray McKinnell, R., Fatheree, P., Choi, S.-K., et al.Discovery of TD-0212, an orally active dual pharmacology AT1 antagonist and neprilysin inhibitor (ARNI)ACS Med. Chem. Lett.10(1)86-91(2018)