Synthesis and Structure-Activity Relationships of Human Renin Inhibitors Designed from Angiotensinogen Transition State

Abstract

The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P₁-P_1, , P₂, and P₄-P₃. Decrease in the size of side chain alkyl group in norstatine analog at P₁ diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P₂, inhibited potently cathepsin D (IC₅₀=6.0×10^-9 M) and pepsin (IC₅₀=3.5×10^-7 M) to the same extent as renin (IC₅₀=8.5×10^-10 M), and thus was not specific for renin. The reduction of the β-carbonyl group to methylene group in β-carbonylpropionyl residue at P₄-P₃ decreased the potency about 2 orders against human renin (5i : IC₅₀=1.1×10^-7 M vs. 1 : IC₅₀=2.4 ×10^-9 M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.