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

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The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P_1-P_<1,>, P_2,and P_4-P_3. Decrease in the size of side chain alkyl group in norstatine analog at P_1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P_2,inhibited potently cathepsin D (IC_<50>=6.0×10^<-9> M) and pepsin (IC_<50>=3.5×10^<-7> M) to the same extent as renin (IC_<50>=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 P_4-P_3 decreased the potency about 2 orders against human renin (5i : IC_<50>=1.1×10^<-7> M vs. 1 : IC_<50>=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.
社団法人日本薬学会の論文
1990-09-25