Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
Krapcho
J
J
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Turk
C
C
Cushman
D W
DW
Powell
J R
JR
DeForrest
J M
JM
Spitzmiller
E R
ER
Karanewsky
D S
DS
Duggan
M
M
Rovnyak
G
G
Schwartz
J
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives*; D004656:Enalapril / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015773:Enalaprilat; D007700:Kinetics; D008297:Male; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D010721:Phosphinic Acids; D004656:Enalapril; D002216:Captopril; D015773:Enalaprilat