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-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.
Gabel
R A
RA
New Lead Pharmacology Merck Research Laboratories, West Point, PA 19486, USA.
Kivlighn
S D
SD
Zingaro
G J
GJ
Schorn
T W
TW
Schaffer
L W
LW
Ashton
W T
WT
Chang
L L
LL
Flanagan
K
K
Greenlee
W J
WJ
Siegl
P K
PK
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D019808:Losartan; D008253:Macaca mulatta; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D002679:Pan troglodytes; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D012083:Renin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C096514:L 159913; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014230:Triazoles; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D019808:Losartan; D011188:Potassium