Studies on angiotensin-converting enzyme inhibitors. I. Syntheses and angiotensinconverting enzyme inhibitory activity of 2-(3-mercaptopropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives.

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Abstract
(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 derived from 6a. Resolution of 3-benzoylthio-2-methylpropionic acid 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 [angiotensin-converting enzyme] inhibitory activity of each isomer of 6a was evaluated. Among them, (3S),(2S)-6a was the most potent inhibitor with an IC50 [median inhibitory concentration] of 8.6 .times. 10-9M. Compound (3S),(2S)-6a induced a dose-dependent inhibition of the pressor response to angiotensin I after oral administration to normotensive anesthetized rats. (3S),(2S)-6a markedly reduced the systolic blood pressure in renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). The in vitro ACE inhibitory activity and the hypotensive effects of (3S),(2S)-6a were comparable to those of captopril.