CGP 38 560: orally active, low-molecular-weight renin inhibitor with high potency and specificity.
CGP 38 560 is a low-molecular-weight (730) inhibitor of human renin that contains only one natural amino acid. In vitro, it is a potent inhibitor of human renin (Ki with tetradecapeptide, 0.4 X 10(-9) M). It has a high enzyme specificity (Ki values against human pepsin, gastricsin, and cathepsin D are 5 X 10(-6), 3 X 10(-6), and 0.6 X 10(-6) M) and is also species specific (IC50 values against human, marmoset, dog, and rat plasma renins are 7 X 10(-10), 7 X 10(-10), 7 X 10(-9), and 1 X 10(-6) M). In vivo, CGP 38 560 inhibits plasma renin activity (PRA) and lowers blood pressure (BP) after oral administration to conscious, normotensive, furosemide-pretreated marmosets. A dose of 10 mg/kg induces complete inhibition of PRA and a decrease in BP of 23 +/- 3 mm Hg (n = 4) after 30 min. These effects persist for up to 2 h. Blockade of the renin-angiotensin system appears to cause the hypotensive response since it is completely prevented by pretreatment with a converting-enzyme inhibitor. These findings demonstrate that the molecular size of renin inhibitors may be reduced to improve their oral activity without loss of potency or specificity.
Wood
J M
JM
Research Department, Ciba-Geigy, Basel, Switzerland.
Criscione
L
L
de Gasparo
M
M
Bühlmayer
P
P
Rüeger
H
H
Stanton
J L
JL
Jupp
R A
RA
Kay
J
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002143:Callitrichinae; D004656:Enalapril / Q000494:pharmacology; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008970:Molecular Weight; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors; D013552:Swine; D013997:Time Factors; D000092502:Renin Inhibitors
D004656:Enalapril; D006830:Hydralazine; D009842:Oligopeptides; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C060150:CGP 38560