French J F, Flynn G A, Giroux E L, Mehdi S, Anderson B, Beach D C, Koehl J R, Dage R C
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
J Pharmacol Exp Ther. 1994 Jan;268(1):180-6.
In the present study we characterize key activities of an agent designed to simultaneously inhibit angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP). MDL 100,240 is a thioester prodrug of MDL 100,173, which is a potent competitive inhibitor of both ACE and NEP in vitro. MDL 100,240 was shown in an ex vivo study to inhibit both of these enzymes in rat kidney. When administered to anesthetized rats, MDL 100,240 enhanced the effect of infused ANP on blood pressure, diuresis and natriuresis and of infused bradykinin on blood pressure. Moreover, MDL 100,173 and MDL 100,240 inhibited the pressor response to angiotensin I. These results indicate that MDL 100,173 and its prodrug, MDL 100,240, produced effects, in vivo, consistent with inhibition of both ACE and NEP.
在本研究中，我们对一种旨在同时抑制血管紧张素I转换酶（ACE）和中性内肽酶（NEP）的药物的关键活性进行了表征。MDL 100,240是MDL 100,173的硫酯前药，MDL 100,173在体外是ACE和NEP的强效竞争性抑制剂。在一项体外研究中，MDL 100,240被证明能抑制大鼠肾脏中的这两种酶。当给麻醉大鼠给药时，MDL 100,240增强了输注的心房利钠肽对血压、利尿和利钠的作用，以及输注的缓激肽对血压的作用。此外，MDL 100,173和MDL 100,240抑制了对血管紧张素I的升压反应。这些结果表明，MDL 100,173及其前药MDL 100,240在体内产生的作用与抑制ACE和NEP一致。
