Inhibitor of angiotensin I converting enzyme: (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS-980)

Pharmacological studies on a new angiotensin I converting enzyme (ACE) inhibitor (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS-980), were carried out in vitro and in vivo. The activity of ACE prepared from rabbit lung by DEAE-Sepharose chromatography was determined using angiotensin I (Ang I) or hippuryl- l-histidyl- l-leucine (HHL) as a substrate. The concentrations of YS-980 producing 50 per cent inhibition of ACE activity (ID 50) when HHL or Ang I was used as a substrate were 9.5 and 13 nM, respectively. The mode of inhibition was competitive, with a K i of 6 nM. Renin activity was not affected by YS-980. Arterial blood pressure was decreased slightly by intravenous injection of YS-980 (0.1 or 1.0mg/kg) to anesthetized rats with or without pretreatment with pentolinium. Pretreatment with YS-980 suppressed the pressor response to Ang I but not to norepinephrine. Intravenous injection of YS-980 (1mg/kg) caused a 21 per cent increase in the pressor response to angiotensin II. These results indicate that YS-980 is a potent and specific inhibitor of ACE.