[In vitro and in vivo inhibition of renin by a thiazolylalanyl cyclostatine derivative].

A compound containing cyclostatine ES-6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4-th iazolyl)- L-alanyl-cyclostatine-(2-morpholinoethyl)amide) was found to be a competitive inhibitor of human renin with an inhibitory constant (Ki) value of 7.3 x 10(-9) M. The compound was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit and rat. ES-6864 did not inhibit cathepsin D, pepsin, urinary kallikrein, angiotensin converting enzyme, trypsin and chymotrypsin at a concentration of 10(-5) M. ES-6864 also inhibited the tissue renin-like activity from dog tissues with IC50 values of 10(-7)-10(-8) M in vitro. Oral administration of ES-6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and a significant inhibition of plasma renin activity, which persisted for 6 hours. Plasma concentration of ES-6864 reached a maximum of 1.2 micrograms/ml at 1 hour after an oral administration. Oral administration of ES-6864 to hog renin-infused rats produced dose-related decreases in blood pressure. The results demonstrate that ES-6864 is an orally active renin inhibitor with high potency and specificity for human renin. Thus, ES-6864 is a candidate compound for development of renin inhibitors that can be used clinically.