Enalaprilat Dihydrate

ACE

348, 4

Male Sprague–Dawley rats

Phase III, has been completed in the extension study of comparing the long-term safety of Valsartan versus Enalapril, and the effectiveness of the combination of Valsartan and Enalapril versus Enalapril alone in children with hypertension.

1 mg/kg

1.94 nM [1], 1.94 nM [1], 1.94 nM [1], 1.94 nM [1], 1.94 nM [1], 1.94 nM [1]

Enalaprilat has unfavourable ionisation characteristics to allow sufficient potency for oral administration, thus Enalaprilat is only suitable for intravenous administration, which is overcome by the esterification with ethanol to produce Enalapril. Administration of Enalaprilat induces a significant reduction of MAP at 70 minutes compared with the placebo group during haemorrhagic shock in rats, and results in a 50% reduction of CO, a general tendency of EB extravasation which is significant in the kidney and lungs, and a significant increase in ileal EB extravasation (53%). [5] Enalaprilat has no effect in nonhypertrophied hearts, but significantly attenuates the greater increase in left ventricular end-diastolic pressure in hypertrophied hearts compared with no drug (65+/-7 versus 50+/-5 mm Hg, p<0.01). [6]

Single displacement binding assay, The binding assay is based on the competitive displacement of [125I]351A by Enalaprilat performed on whole endothelial cells. Subconfluent HUVECs in 6-well plates are rinsed with 2 mL binding buffer (140 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl2, 1.03 mM MgCl2, 0.42 mM NaH2PO4, 10 mM HEPES, 2 mM sodium pyruvate and 5 mM glucose, pH 7.4), and the culture medium is replaced with 2.5 mL fresh binding buffer containing 5% fetal bovine serum (FBS). The Enalaprilat (2.5-12.5 uL, 0.1-50 nM) or equivalent volumes of diluent are added to the binding buffer. A saturating amount of [125I]351A (10 uL, typically 106 cpm) is then added to each sample and the plates are incubated at 37 C for 2 hours in a thermostatic bath. The cells are then rinsed twice with 1.5 mL binding buffer. Finally, the cells are extracted with 0.5 mL NaOH 1 N, incubated for 5 minutes, and the radioactivity is counted with a gamma counter. The ratio of specific [125I]351A bound to total bound activity (B/B0) is calculated, and the inhibitory potency of Enalaprilat expressed as the concentration of ACE inhibitors able to displace 50% of the bound radioligand, i.e. the IC50.

DMSO 70 mg/mL, Water 5 mg/mL, Ethanol 1 mg/mL

Enalaprilat is the first dicarboxylate-containing ACE inhibitor developed partly to overcome limitations of captopril.