Effect of N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro and its ethyl ester (MK-421) on angiotensin converting enzyme in vitro and angiotensin I pressor responses in vivo.
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) 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. Similarly 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 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/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 p.o. for at least 6 hr 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 ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.
D000284:Administration, Oral; D000758:Anesthesia; D000803:Angiotensin I / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004656:Enalapril; D015773:Enalaprilat; D004951:Esterification; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D004151:Dipeptides; D004656:Enalapril; D000803:Angiotensin I; D002216:Captopril; D015773:Enalaprilat; D001920:Bradykinin