Biology of a novel class of potent long-acting angiotensin converting enzyme inhibitors

The acyl lysinamido phosphonates represent a novel class of angiotensin I converting enzyme (ACE) inhibitors. Representatives of this class produce 50% inhibition of purified rabbit lung ACE at concentrations less than 8 nmol/l. After intravenous and oral administration to normotensive rats the phosphonates inhibited an angiotensin I pressor response by 50% at doses less than or equal to enalapril (oral studies) or its free acid, MK-422 (intravenous studies); however, the duration of effect was much longer after the phosphonates. In conscious cynomolgus monkeys, representatives of the phosphonate class showed greater inhibition of an angiotensin I pressor response and for a much longer period of time than enalapril, fosinopril and lisinopril. Similarly, in sodium-depleted monkeys the blood pressure lowering effects of enalapril, lisinopril and fosinopril were of short duration compared with those of the phosphonates. It is concluded that the acyl lysinamido phosphonates represent a potent and long-acting class of ACE inhibitors in vitro and in vivo.