Some in vitro and in vivo studies of a new angiotensin I‐converting enzyme inhibitor [[S‐(R*), S*]‐1‐[(3‐acetylthio)‐3‐benzoyl‐2‐methylpropionyl]‐L‐proline] (CL 242,817) in comparison with captopril

Some in vitro and in vivo properties of CL 242,817, a new angiotensin l‐converting enzyme (ACE) inhibitor, were studied and compared to those of captopril. In vitro CL 242,817 effectively inhibited rabbit lung ACE (IC50 54.9 nM), angiotensin l (Al)‐induced contractions (IC50 0.82 μM), and potentiated bradykinin (BK)‐induced contractions (EC50 0.383μM) of the guinea pig ileum. In these systems, CL 242,817 was approximately 3.5, 27, and 96 times less effective than captopril, respectively. In vivo, equimolar oral doses of CL 242,817 (8.36 mg/kg) and captopril (5 mg/kg) were equieffective in inhibiting the pressor responses to intravenously (i.v.) administered angiotensin l (Al) in normotensive rats and dogs. Similar equimolar oral doses of CL 242,817 and captopril were also equieffective in potentiating the depressor responses to i.v. administered BK in the rat. In the anesthetized dog 30 min after dosing, captopril (0.5 mg/kg i.v.) produced significantly greater potentiation of the BK response than a similar dose of CL 242,817. A single 1 mg/kg i.v. dose of Cl 242,817 or captopril effectively lowered mean arterial blood pressure of the aortic‐coarcted hypertensive rat (AHR) and markedly inhibited serum ACE activity after 1 hr. Serum from AHR treated with CL 242,817 or captopril exhibited an apparent loss in ACE inhibition upon cold storage. However, the loss of inhibition of ACE activity was faster with captopril than with CL 242,817. Kinetic studies indicate that CL 242,817 is a pure competive inhibitor of ACE with an estimated Ki of 24.3 nM.