Preclinical Pharmacology of Zofenopril, an Inhibitor of Angiotensin I Converting Enzyme

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Abstract
Summary: Zofenopril calcium (one-half calcium salt) is a prodrug ester analog of captopril whose biological effects are manifested by its active component, SQ 26,333. Because of the relative insolubilities of both zofenopril calcium and SQ 26,333, zofenopril potassium salt and SQ 26,703, the arginine salt of the active ACE (angiotensin I converting enzyme) inhibitory moiety of zofenopril, were employed in many of the following studies. The in vitro and in vivo pharmacological effects of zofenopril have been evaluated and comparisons have been made to captopril. In vitro, SQ 26,703 was more potent than captopril as an inhibitor of rabbit lung ACE (IC50 = 8 vs. 23 nM). SQ 26,703 was also a potent inhibitor of angiotensin I (AI)-induced contractions (EC50 = 3 nM) and a potentiator of bradykinin-induced contractions (EC50 = 1 nM) of isolated guinea pig ileum, while it had no effect on the inotropic effects of angiotensin II, BaCl2, PGE1, histamine, serotonin, or acetycholine in the same tissue, signifying that zofenopril is a specific inhibitor of ACE. In vivo, the potency of SQ 26,703 was equal to or greater than that of captopril as an inhibitor of an AI pressor response when given intravenously to rats, dogs, and monkeys. After oral administration of equimolar doses, zofenopril was the more effective and longer lasting ACE inhibitor in all three species. In SHR, doses of 6.6 and 22.0 mg/kg, p.o. lowered pressure by 20 and 33 mm Hg, respectively, while 30 mg/kg of captopril lowered pressure by 25 mm Hg. Zofenopril's effects were longer lasting. A combination of zofenopril and hydrochlorothiazide lowered pressure more (34 mm Hg) than zofenopril alone (20 mm Hg) in SHR. In two-kidney, one-clip renal hypertensive rats, zofenopril was more effective than captopril as an antihypertensive and again zofenopril's effects lasted longer. In anesthetized dogs, zofenopril had no effect on catecholamine-induced pressor responses or reflex changes in blood pressure and heart rate during head-up tilting or bilateral carotid artery occlusion. It is concluded that zofenopril is an effective and long lasting inhibitor of ACE in rats, dogs, and monkeys and an effective antihypertensive agent in rats.