Studies on angiotensin converting enzyme inhibitors. 4. Synthesis and angiotensin converting enzyme inhibitory activities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acid derivatives.
(4S)-1-Alkyl-3-[[N-(carboxyalkyl)amino]acyl]-2-oxoimidazolidine-4- carboxylic acid derivatives (3) were prepared by two methods. Their angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationships were discussed. The dicarboxylic acids 3a-n possessing S,S,S configuration showed potent in vitro ACE inhibitory activities with IC50 values of 1.1 X 10(-8)-1.5 X 10(-9) M. The most potent compound in this series, monoester 3p, had an ID50 value of 0.24 mg/kg, po for inhibition of angiotensin I induced pressor response in normotensive rats and produced a dose-dependent decrease in systolic blood pressure of spontaneously hypertensive rats (SHRs) at doses of 1-10 mg/kg, po.
Hayashi
K
K
Research Laboratory of Applied Biochemistry and Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Nunami
K
K
Kato
J
J
Yoneda
N
N
Kubo
M
M
Ochiai
T
T
Ishida
R
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D002264:Carboxylic Acids; D007093:Imidazoles