Terlakiren - An Orally-Active Renin Inhibitor In The Guinea-Pig

Human and monkey renin are very similar, but differ from the renin of species commonly used in screening antihypertensive agents (i.e., dog and rat). This has necessitated the evaluation of renin inhibitors (Rls) in primate models. We have found that many Rls are also active against guinea pig (GP) renin, and thus may be evaluated for mean arterial pressure (MAP) lowering in this species. One such RI is terlakiren (isopropyl N-[N-(4-morpholinocarbonyl)-L-phenylalaninyl-S-methyl-L-cysteinyl]-2-(R)-hydroxy-3(S)-amino-4-cyclohexybutanoate, formerly CP-80,794), an orally active renin inhibitor which lowers MAP and plasma renin activity (PRA) in sodium-deficient cynomolgus and marmoset monkeys. In vitro, terlakiren's IC50 against primate renin (including man) is similar to 0.6 and 0.3 nM against GP renin. At iv doses of 0.3-3.0 mg (0.48-4.8 mu mol)/kg in sodium-depleted GPs, terlakiren produced 20-30 mmHg falls in MAP which returned to control values in 30-150 min. Oral administration of terlakiren at 30 mg (48.3 mu mol)/kg reduced MAP 10-15 mmHg and MAP returned to control levels in similar to 150 min. Increasing the dose of terlakiren to 50 mg (81 mu mol)/kg (po) decreased MAP 25-30 mmHg, with a total duration of effect >5 h. Cardiac output and heart rate were unaffected, indicating that the fall in MAP was totally due to decreased total peripheral resistance. Terlakiren had minimal effects on MAP in GPs on a normal sodium diet. The effect of terlakiren on PRA was evaluated in separate studies. Control PRAs for the sodium-deficient GPs ranged from 15-20 ng Al/ml/h. After 50 mg (87 mu mol)/kg (po) of terlakiren, there was 81% suppression of PRA (vs. control) at 240 min and 62% suppression at 5 h. Thus, terlakiren was orally active against renin and blood pressure in the sodium-depleted guinea pig, which appears to be a very good non-primate alternative for the evaluation of renin inhibitors. (C) 1995 Wiley-Liss, Inc.