Syntheses and Biological Activities of Renin Inhibitors Containign Statine Analogues

Syntheses and biological activities of dipeptide renin inhibitors that contain statine analogues are described. The key steps fo the synthetic approach to dipeptide renin inhibitors are the asymmetric synthesls of 2(R)-substituted-3-aminocarbonylpropionic acids and the diastereoselective syntheses of (3S, 4S)-statine analogues. These inhibitors (2, 14-40) inhibited human renin in the 3-140 nM range. Inhibitor ES 6864 (2) was found to be a highly potent inhibitor of human renin (IC50 : 4.6×10-9M) and showed high enzyme specificity. Oral administration of ES 6864 at 3 mg/kg to conscious, sodium-depleted marmosets inhibted plasma renin activity (PRA) more than 80% after 1h.