A novel human renin inhibitor with a retro-inverso amide bond demonstrated oral bioavailability and blood pressure-lowering efficacy in a primate model.
Supports advancement of retro-inverso renin inhibitors; leaves open translation to human hypertension therapy.
The experimental details for the synthesis of human renin inhibitors are described. In order to avoid metabolic degradation of the Phe-His (P3-P2) amide bond in transition-state analogs, structurally modified acyl residues (P4-P3) were incorporated into the inhibitors. Compound 1a, which contained 2-(1-naphthylmethyl)-3-(N-phenethylcarbamoyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and norstatine isoamylamide residue (P1-P1) as a transition-state mimic, had potent human renin inhibitory activity, and it lowered blood pressure when administered orally to common marmosets.
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Kamijo et al. (1990) studied this question.
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