EFFECT OF N-[(S)-1-CARBOXY-3-PHENYLPROPYL]-L-ALA-L-PRO AND ITS ETHYL-ESTER (MK-421) ON ANGIOTENSIN CONVERTING ENZYME INVITRO AND ANGIOTENSIN-I PRESSOR-RESPONSES INVIVO

  • 1 January 1981
    • journal article
    • research article
    • Vol. 216  (3) , 552-557
Abstract
The parent diacid N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) [50% inhibition] at a concentration of 1.2 nM, and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. In the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 [median inhibitory dose] of 8.2 .mu.g/kg i.v. in rats and 6.4 .mu.g/kg i.v. in dogs. The diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 .mu.g/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg per os, for at least, 6 h in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of this supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significance in vivo pharmacological activity.

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