Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives.
A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.
Suh
J T
JT
Skiles
J W
JW
Williams
B E
BE
Youssefyeh
R D
RD
Jones
H
H
Loev
B
B
Neiss
E S
ES
Schwab
A
A
Mann
W S
WS
Khandwala
A
A
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000627:therapeutic use; D013440:Sulfides / Q000138:chemical synthesis / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D013438:Sulfhydryl Compounds; D013440:Sulfides; D005998:Glycine