Antihypertensive assessment of two new angiotensin‐converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934

Abstract

Abstract CGS 13945 (1‐(4‐(ethoxycarbonyl)‐2,4‐dimethyl‐2R,4R‐butyryl)‐2,3‐dihydro‐2S‐indole‐2‐carboxylic acid) and CGS 13934 (its dicarboxylic acid derivative) are nonthiol angiotensin‐converting enzyme (ACE) inhibitors which have antihypertensive properties. Acute administration of CGS 13945 lowers systolic pressure in spontaneously hypertensive rats (SHR) and sodium depletion enhances the blood pressure reduction; the acute antihypertensive effects of CGS 13934 are minimal. Acute administration of CGS 13945 or CGS 13934 also elevates plasma renin activity, especially in sodium‐depleted SHR. CGS 13945 reduces systolic blood pressure of SHR in a dose‐dependent manner following oral administration on each of 4 consecutive days, whereas the antihypertensive effect of CGS 13934 is not apparent until the third day of drug administration. After 3 consecutive daily doses, 30 mg/kg (PO) of CGS 13945, CGS 13934 or captopril produce equal antihypertensive effects. CGS 13945 also reduces systolic blood pressure of sodium‐depleted normotensive rats. Daily oral administration of CGS 13945 to either sodium‐replete or ‐deplete perinephritic hypertensive dogs does not appreciably affect mean arterial pressure. Results suggest that CGS 13945 must be endogenously de‐esterified to the free acid form for endowment of optimal biological activity to inhibit the ACE. While the rat is apparently capable of such hydrolysis, the dog's capacity for endogenous hydrolysis appears to be quite limited.