RENIN INHIBITORS CONTAINING A PYRIDYL AMINO DIOL DERIVED C-TERMINUS

Based on the concept of transition-state analogs, a series of nonpepti de renin inhibitors with the new ino-1-cyclohexyl-3,4-dihydroxy-6-(2-p yridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All c ompounds exhibited potencies in the nanomolar or even subnanomolar ran ge when tested versus human renin in vitro. Selected inhibitors were e valuated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduo denal administration of a dose of 2 mg/kg. Compound 38 (S 2864) contai ning an amino piperidyl succinic acid derived N-terminal is the most p romising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decre ased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetize d, sodium-depleted rhesus monkeys.