A Highly Potent and Long-Acting Oral Inhibitor of Human Renin

A Highly Potent and Long-Acting Oral Inhibitor of Human Renin

An orally active renin inhibitor, ES 6864 (JV-(2R)-3-morpholinocarbonyl-2-(l-naphthylmethyl) propionyl]-(4-thiazoIyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a value of 7.3 × 10 M. The compound competitiv...

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Bibliographic Details
Published in:Hypertension (Dallas, Tex. 1979) Vol. 11; no. 6, Part 2; pp. 708 - 712
Main Authors: HIWADA, KUNIO, KOKUBU, TATSUO, MURAKAMI, EIKJ, MUNETA, SHINJIRO, MORISAWA, YASUHIRO, YABE, YUICHIRO, KOIKE, HIROYUKJ, IUIMA, YASUTERU
Format: Journal Article
Language:English
Published: United States American Heart Association, Inc 01-06-1988
Subjects:
Administration, Oral
Animals
Callitrichinae
Dipeptides - pharmacology
Dogs
Goats
Humans
Male
Morpholines - pharmacology
Protease Inhibitors - pharmacology
Rabbits
Rats
Rats, Inbred Strains
Renin - antagonists & inhibitors
Species Specificity
Swine
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Summary:An orally active renin inhibitor, ES 6864 (JV-(2R)-3-morpholinocarbonyl-2-(l-naphthylmethyl) propionyl]-(4-thiazoIyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a value of 7.3 × 10 M. The compound competitively inhibited human renin. The inhibitor 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, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10 M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin Inhibitors that can be used clinically.
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ISSN:0194-911X
1524-4563
DOI:10.1161/01.hyp.11.6.708