Angiotensin-converting enzyme inhibitors: perhydro-1,4-thiazepin-5-one derivatives.
alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.
Yanagisawa
H
H
Chemical Research Laboratory, Sankyo Co., Ltd., Tokyo, Japan.
Ishihara
S
S
Ando
A
A
Kanazaki
T
T
Miyamoto
S
S
Koike
H
H
Iijima
Y
Y
Oizumi
K
K
Matsushita
Y
Y
Hata
T
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D008297:Male; D008968:Molecular Conformation; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D013841:Thiazepines