EFFECTS OF THE RENIN INHIBITOR CLOHEXYL-3,4-DIHYDROXY-6(2-PYRIDYL)-HEXANE-2-AMIDE ACETATE IN ANESTHETIZED RHESUS-MONKEYS

The renin inhibitory effect of the non-peptide renin inhibitor S 2864 (N-[N-(3-(4-Amino-1-piperidinyl-carbonyl)-2 (R)- benzylpropionyl)-L-hi stidinyl]-(2S, 3R, 4S)-1-cyclohexyl-3, 4-dihydroxy-6(2-pyridyl)-hexane -2-amide acetate, CAS 135683-92-0) was characterized in vitro and in v ivo in primates. In vitro, S 2864 inhibited the activity of purified h uman plasma renin with an IC50 of 3.8 x 10(-10) mol/l and did not affe ct related human aspartyl proteases like human cathepsin E, cathepsin D or pepsin. In vivo, in anesthetized sodium depleted rhesus monkeys S 2864 decreased mean arterial blood pressure after intraduodenal (i. d .) administration of 2 mg/kg significantly by 27 % from 94 +/- 8 to 62 +/- 6 mmHg for 90 min. Heart rate was not changed. Cumulative intrave nous (i. v.) administration of S 2864 of remikiren in doses of 1, 10 a nd 30 mu g/kg significantly decreased systemic blood pressure, dP/dt(m ax) and cardiac output while heart rate was not changed. Plasma angiot ensin II (ANG II) levels as well as renin activity were dose dependent ly reduced after 10, 30 and 60 min. It is concluded that S 2864 is an effective specific inhibitor of human renin eliciting marked blood pre ssure lowering activities in primates.