CGS 30440: A dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase 24.11

For nearly two decades, angiotensin converting enzyme (ACE) inhibitors have been used in the management of hypertension and as adjunctive therapy in the treatment of congestive heart failure (15,26,27). Clinical studies have demonstrated that ACE inhibitors decrease the morbidity and mortality following myocardial infarction (49) and prevent heart failure in patients with left ventricular dysfunction (50,63). Captopril, the first ACE inhibitor discovered in 1975, has been approved for the treatment of nephropathy associated with type 1 diabetes mellitus (38). Clearly, the success achieved with ACE inhibitors in the management of cardiovascular diseases demonstrates the important role that the renin-angiotensin system plays in the etiology of these conditions. Upon the demonstration that neutral endopeptidase (NEP) 24.11 was the enzyme responsible for the degradation of the endogenous vasodilator and natriuretic hormone, atrial natriuretic peptide (ANP; 17,34,45), interest grew in the inhibition of this enzyme as a new therapeutic approach to hypertension and heart failure. Intravenous infusions of ANP reduce blood pressure while causing diuresis and increased urinary excretion of sodium and cGMP (32). Short-term studies of renal failure in rats with reduced renal mass have demonstrated some improvement in renal function with the use of phosphoramidon, a NEP inhibitor (36,72). As a result, several NEP inhibitors have been evaluated clinically for the treatment of hypertension and congestive heart failure (CHF). In one study involving patients with essential hypertension, substantial lowering of blood pressure was observed (44). However, most clinical trials have reported modest or no significant effects (7,43,54–57). Consequently, meaningful clinical improvements in the treatment of any cardiovascular disease with this class of compound have yet to be established.