Studies on Angiotensin-converting Enzyme Inhibitors. I. Syntheses and Angiotensin-converting Enzyme Inhibitory Activity of 2-(3-Mercaptopropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid Derivatives
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概要
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(3S)-2-[(2S)-3-Mercapto-2-methylpropionyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [(3S), (2S)-6a] was prepared by the reaction of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester [(3S)-2a] or benzyl ester [(3S)-2b] with 3-benzoylthio-2-methylpropionyl chloride (3a), followed by fractional crystallization and removal of the protective group. The absolute configuration of (3S), (2S)-6a was confirmed by X-ray diffraction analysis of the thiazepino [4,3-b] isoquinoline compound (7) derived from 6a. Resolution of 3-benzoylthio-2-methylpropionic acid (8) was completed by using optically active phenylalanine amide as a resolving agent. The other optical isomers of (3S), (2S)-6a were prepared by the reaction of (3S)- or (3R)-2b with optically active 3a. The in vitro ACE inhibitory activity of each isomer of 6a was evaluated. Among them, (3S), (2S)-6a was found to be the most potent inhibitor with an IC_<50> value of 8.6×10^<-9>M. Compound (3S), (2S)-6a induced a dose-dependent inhibition of the pressor response to angiotensin I after oral administration to normotensive anesthetized rats. Moreover, (3S), (2S)-6a markedly reduced the systolic blood pressure in renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). The in vivo ACE inhibitory activity and the hypotensive effects of (3S), (2S)-6a were comparable to those of captopril.
- 1983-02-25
著者
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沼波 憲一
生化研
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米田 直人
Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd.
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米田 直人
Research Laboratory Of Applied Biochemistry Tanabe Seiyaku Co. Ltd.
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加藤 錠治
Research Laboratory Of Applied Biochemistry Tanabe Seiyaku Co. Ltd.
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内田 奉典
田辺製薬(株)応用生化学研究所
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尾崎 泰彦
Research Laboratory of Applied Biochemistry Tanabe Seiyaku Co., Ltd.
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木梨 計三
Safety Research Laboratory Tanabe Seiyaku Co., Ltd.
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尾崎 泰彦
Research Laboratory Of Applied Biochemistry Tanabe Seiyaku Co. Ltd.
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林 公明
Research Laboratory Of Applied Biochemistry:tanabe Seiyaku Co. Ltd.
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木梨 計三
Safety Research Laboratory Tanabe Seiyaku Co. Ltd.
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米田 直人
Research Laboratory of Applied Biochemistry
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米田 直人
Research Laboratory of Applied Biochemistry Tanabe Seiyaku Co., Ltd.
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