CGP 38 560: Orally Active, Low-Molecular-Weight Renin Inhibitor with High Potency and Specificity

CGP 38 560 is a low-molecular-weight (730) inhibitor of human renin that contains only one natural amino acid. In vitro, it is a potent inhibitor of human renin (Ki with tetradecapeptide, 0.4 × 10 M). It has a high enzyme specificity (Ki values against human pepsin, gastricsin, and cathepsin D are 5 × 10, 3 × 10, and 0.6 × 10 M) and is also species specific (IC50 values against human, marmoset, dog, and rat plasma renins are 7 × 10, 7 ± 10-10, 7 × 10, and 1 × 10 M). In vivo, CGP 38 560 inhibits plasma renin activity (PRA) and lowers blood pressure (BP) after oral administration to conscious, normotensive, furosemide-pretreated marmosets. A dose of 10 mg/kg induces complete inhibition of PRA and a decrease in BP of 23 ± 3 mm Hg (n = 4) after 30 min. These effects persist for up to 2 h. Blockade of the renin-angiotensin system appears to cause the hypotensive response since it is completely prevented by pretreatment with a converting-enzyme inhibitor. These findings demonstrate that the molecular size of renin inhibitors may be reduced to improve their oral activity without loss of potency or specificity.