In vivo pharmacology of L-159,913, a new highly potent and selective nonpeptide angiotensin II receptor antagonist

• Published in: Clinical and experimental hypertension (1993) Vol. 17; no. 6; p. 931
• Main Authors: Gabel, R A, Kivlighn, S D, Zingaro, G J, Schorn, T W, Schaffer, L W, Ashton, W T, Chang, L L, Flanagan, K, Greenlee, W J, Siegl, P K
• Format: Journal Article
• Language: English
• Published: England 1995
• Subjects: Aldosterone - blood; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents - pharmacology; Biphenyl Compounds - pharmacology; Blood Pressure - drug effects; Dogs; Female; Hypertension - drug therapy; Hypertension - physiopathology; Imidazoles - pharmacology; Kidney - drug effects; Kidney - physiology; Losartan; Macaca mulatta; Male; Natriuresis - drug effects; Pan troglodytes; Potassium - urine; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin - drug effects; Receptors, Angiotensin - physiology; Renin - physiology; Tetrazoles - pharmacology; Triazoles - pharmacology
• ISSN: 1064-1963
• DOI: 10.3109/10641969509033644

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2'-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydr o-2- [2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED50) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.