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

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-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazcl-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-l59,913 had a moderate diuretic, n...