Antihypertensive MDL-100240
Various strategies are used to reduce arterial blood pressure. Of particular importance are drugs that act on the renin-angiotensin system, which regulates blood pressure and the electrolyte and fluid balance within the body. Such drugs include ACE inhibitors.
Most current therapies focus on diastolic blood pressure, which is considered high if it exceeds 90 mmHg. But it is now thought that a systolic blood pressure in excess of 140 mmHg poses a greater threat, and so scientists are looking for potential medicines that would act more effectively on the systolic blood pressure. Aventis is investigating MDL-100240,1 which inhibits both ACE and neprilysin, the neutral endopeptidase, NEP. Both are zinc-containing metalloproteases that are involved in the biosynthesis and activation of peptides that mediate cardiovascular and renal activities. If both of these enzymes were to be inhibited at the same time, it should lower the activity of the renin-angiotensin system, while enhancing the vasodilating and antiproliferative effects of bradykinin and other hormones, leading to a lowering of blood pressure and decreased vascular tone.
MDL-100240 is an orally-active thioester pro-drug. A study in 12 healthy volunteers with high or low sodium intake (280 or 80mmol/day) looked at the effect of a single dose of the drug, either 6.25 or 25mg given intravenously over 20min. It decreased the supine systolic blood pressure after two hours in high sodium patients by 8 mmHg with the high dose and 4 mmHg with the lower dose. Similarly, it reduced systolic blood pressure in low sodium patients. A rapid, dose-related reduction in plasma ACE was seen, plasma angiotensin II levels decreased, and plasma renin activity rose. The main side-effect observed was headache, and diastolic blood pressure and heart rate were unaffected.2
The drug is now undergoing Phase IIb studies for the treatment of both high blood pressure and congestive heart failure.