Miller K E, Huang C T, Portlock D E, Wright G C
Life Sci. 1987 Jan 5;40(1):63-70. doi: 10.1016/0024-3205(87)90253-0.
The activity of three angiotensin I converting enzyme (ACE) inhibitors with unique related structures was assessed in vitro and in vivo. The three compounds were (S)(-)-1,2,3,4-tetrahydro-2-(3-mercapto-1-oxopropyl)-3-isoquinoline carboxylic acid (EU-4865), 1,2,3,4-tetrahydro-2-(3-mercapto-1-oxopropyl)-1- isoquinolinecarboxylic acid (EU-4881), and (S)(-)-1,2,3,4-tetrahydro-1-(3-mercapto-1-oxopropyl)-2- quinolinecarboxylic acid (EU-5031). In vitro EU-4881 was a competitive inhibitor that lacked potency (IC50 = 1980 nM) against purified ACE. The other two compounds were equipotent (IC50 = 41 nM) against purified ACE but differed in their inhibition kinetics. EU-4865 (Ki = 38 nM) was a noncompetitive inhibitor, and EU-5031 (Ki = 6.9 nM) was a competitive inhibitor. Against caveolae membrane-bound ACE EU-4881 also lacked potency (IC50 = 2852 nM). In vivo in the conscious acute aortic coarctate (AAC) rat it also lacked potency, having an ED30 (oral dose decreasing blood pressure 30 mmHg) greater than 100 mg/kg. The activity of EU-4865 and EU-5031 in the caveolae membrane-bound ACE and AAC rat reflected their different Ki values rather than their similar IC50 values. In vitro, EU-4865 and EU-5031 had IC50 values of 19 and 6.7 nM, respectively, and in vivo, they had ED30 values of 52 and 1.1 mg/kg, respectively. These results suggest that ACE has a binding requirement for a carboxy-terminus, hydrophobic amino acid that is important for in vivo activity.
对三种具有独特相关结构的血管紧张素I转换酶（ACE）抑制剂进行了体外和体内活性评估。这三种化合物分别是（S）（-）-1,2,3,4-四氢-2-（3-巯基-1-氧代丙基）-3-异喹啉羧酸（EU-4865）、1,2,3,4-四氢-2-（3-巯基-1-氧代丙基）-1-异喹啉羧酸（EU-4881）和（S）（-）-1,2,3,4-四氢-1-（3-巯基-1-氧代丙基）-2-喹啉羧酸（EU-5031）。在体外，EU-4881是一种竞争性抑制剂，对纯化的ACE缺乏效力（IC50 = 1980 nM）。其他两种化合物对纯化的ACE具有同等效力（IC50 = 41 nM），但抑制动力学不同。EU-4865（Ki = 38 nM）是非竞争性抑制剂，EU-5031（Ki = 6.9 nM）是竞争性抑制剂。对于小窝膜结合的ACE，EU-4881同样缺乏效力（IC50 = 2852 nM）。在清醒急性主动脉缩窄（AAC）大鼠体内，它也缺乏效力，其ED30（使血压降低30 mmHg的口服剂量）大于100 mg/kg。EU-4865和EU-5031在小窝膜结合的ACE和AAC大鼠中的活性反映了它们不同的Ki值，而非相似的IC50值。在体外，EU-4865和EU-5031的IC50值分别为19和6.7 nM，在体内，它们的ED30值分别为52和1.1 mg/kg。这些结果表明，ACE对羧基末端的疏水性氨基酸有结合需求，这对体内活性很重要。
