New Inhibitors of Human Renin That Contain Novel Replacements at the P2 Site

Article abstract of DOI:10.1021/jm00108a004

A series of renin inhibitors with novel modifications at the P₂ site has been prepared.Structure-activity relationships reveal that for a particular P₂ fragment the in vitro potency is highly dependent on the nature of the P₂' portion in addition to the P₁-P₁' group.The length of the P₂ side chain and choice of ε-N P₂ substitution have been found to be important for in vitro potency although the degree of unsaturation in the P₂ side chain is not particularly significant.Molecular modeling studies have shown that it is possible for the P₂ side chain to interact unfavorably with the P₂' bi nding site.It has been possible to control the specificity for renin over cathepsin D by correct modification at the P₂' and P₁-P₁' sites.Variations at the P₄ site have been utilized to lower the log P values of these renin inhibitors while maintaining high potency.Compound 42, which exhibited an IC50 of 3.70 nM, log P of 2.3, and showed high specificity for renin, was selected for further studies.It was found to be very stable under neutral, acidic, and basic conditions.In simulated intestinal juice, compound 42 had a half-life of 37 min while it was virtually unaffected by simulated gastric juice after 4 h.Compound 42 produced a significant hypotensive response upon intravenous administration to the salt-depleted normotensive cynomolgus monkey.