Effects of SC-56525, a Potent, Orally Active Renin Inhibitor, in Salt-Depleted and Renal Hypertensive Dogs

Abstract

Abstract SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1±16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.