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Dual ACE and NEP Inhibitors:A Review of the Pharmacological Properties of MDL 10

     The Angiotensin I converting enzyme (ACE, EC, kininase II) and neutral

    endopeptidases (NEP, NEP 24.11) are mechanistically related metallopeptidases. They

    play a key role in the regulation of blood pressure, body fluid homeostasis and cell

    growth. Therefore, they are implicated in the pathogenesis of arterial hypertension, congestive heart failure, left ventricular remodeling after myocardial infarction and other

    cardiovascular diseases. Furthermore, since these two metallopeptidases possess some

    subsite and substrate similarities, as indicated by their interaction with certain mercaptoalkanoyl inhibitors, they are regarded as an important common target for pharmacological inhibition with a single drug. MDL 100,240 is a pro-drug that, upon conversion to MDL 100,173, acts as a potent dual inhibitor of ACE and NEP with a balanced activity on both enzymes. Only very limited pharmacokinetic studies with MDL 100,240 have been published. These studies used a high pressure liquid chromatography method with UV

    absorbance detection to quantify the drug. According to the studies in dogs the terminal

    t1_2 of MDL 100,173 was 35.7 h. The area under the curve for total MDL 100,173 was

    nearly 10-fold greater than the sum of the areas under the curve for MDL 100,240 and for

    unconjugated MDL 100,173. These results support the hypothesis that MDL 100,240 is

    hydrolyzed in plasma to the active thiol, MDL 100,173, which is rapidly conjugated with

    endogenous plasma thiols thus providing a pathway for elimination. Studies in vivo in experimental models of hypertension and congestive heart failure confirmed the vasodilatory

    and natriuretic effects of MDL, which appear to be independent of the degree of activation

    of the renin-angiotensin-aldosterone system. In addition, MDL 100,240 showed an

    impressive effectiveness both in preventing and in regressing hypertension-induced vas-

    cular remodeling and cardiac hypertrophy. Accordingly, MDL 100,240 is being developed

    for the treatment of cardiovascular diseases, including hypertension and congestive heart

    failure. If the promises of this novel therapeutic strategy are fulfilled, clinical trials are expected to demonstrate advantages of MDL 100,240 over pure ACE inhibitors.