Characterization of a dual inhibitor of angiotensin I-converting enzyme and neutral endopeptidase.
In the present study we characterize key activities of an agent designed to simultaneously inhibit angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP). MDL 100,240 is a thioester prodrug of MDL 100,173, which is a potent competitive inhibitor of both ACE and NEP in vitro. MDL 100,240 was shown in an ex vivo study to inhibit both of these enzymes in rat kidney. When administered to anesthetized rats, MDL 100,240 enhanced the effect of infused ANP on blood pressure, diuresis and natriuresis and of infused bradykinin on blood pressure. Moreover, MDL 100,173 and MDL 100,240 inhibited the pressor response to angiotensin I. These results indicate that MDL 100,173 and its prodrug, MDL 100,240, produced effects, in vivo, consistent with inhibition of both ACE and NEP.
French
J F
JF
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
Flynn
G A
GA
Giroux
E L
EL
Mehdi
S
S
Anderson
B
B
Beach
D C
DC
Koehl
J R
JR
Dage
R C
RC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D011355:Prodrugs; D011725:Pyridines; C085683:MDL 100240; C085684:MDL 100173; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D001920:Bradykinin