CHARACTERIZATION OF A DUAL INHIBITOR OF ANGIOTENSIN I-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE

In the present study we characterize key activities of an agent design ed to simultaneously inhibit angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP). MDL 100,240 is a thioester prodrug of MD L 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 o f these enzymes in rat kidney. When administered to anesthetized rats, MDL 100,240 enhanced the effect of infused ANP on blood pressure, diu resis and natriuresis and of infused bradykinin on blood pressure. Mor eover, MDL 100,173 and MDL 100,240 inhibited the presser response to a ngiotensin 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.