An ACE and NEP inhibitor
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)
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Kinase experiment: |
Omapatrilat is dissolved in 100% DMSO at 10 mM and diluted to 1% DMSO. NEP, NEP2, ACE and APP assays are performed at pH 7.4. The reaction buffer for NEP and NEP2 contained 50 mM HEPES, 140 mM NaCl, 10 mM KCl, 0.01% BSA. The buffer for ACE contained 100 mM Tris-HCl, 50 mM NaCl, 10 μM ZnCl2, and the buffer for APP contained 100 mM HEPES and 0.01% BSA. Assays are performed in 100 μL volume in black 96-well round-bottom plates at room temperature. Reactions are continuously monitored with excitation and emission wavelengths appropriate for each respective substrate. Enzyme velocity is determined from the linear part of the reaction[1]. |
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Animal experiment: |
Rats: Sprague Dawley rats are weighed and then gavaged with vehicle (5% arabic gum) or omapatrilat (0.1, 1, 10 mg/kg) (n 5 6 rats/group). Rats are killed by decapitation at 1 h after gavage. Trunk blood is collected into prechilled tubes containing EDTA/aprotinin for the measurement of PRA and into prechilled heparin tubes for the measurement ofplasma ACE[4]. Rabbits: Omapatrilat is dissolved in drinking water. Rabbits are divided into 2 groups with 1% cholesterol diet, placebo-treated group and omapatrilat-treated group, and administrated (12 mg/Kg/day omapatrilat) once daily for 8 weeks. To demonstrate the acute effect of omapatrilat, urine is collected after omapatrilat or placebo administration for 24 hours at day 1, and urine volume, cGMP and ANP levels are assessed[3]. |
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参考文献: [1]. Fryer RM, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy ofenzymes associated with bradykinin-mediated angioedema.Br J Pharmacol. 2008 Mar;153(5):947-55. |
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