PT  - JOURNAL ARTICLE
AU  - P K Siegl
AU  - R S Chang
AU  - N B Mantlo
AU  - P K Chakravarty
AU  - D L Ondeyka
AU  - W J Greenlee
AU  - A A Patchett
AU  - C S Sweet
AU  - V J Lotti
TI  - In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist.
DP  - 1992 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 139--144
VI  - 262
IP  - 1
4099  - http://jpet.aspetjournals.org/content/262/1/139.short
4100  - http://jpet.aspetjournals.org/content/262/1/139.full
SO  - J Pharmacol Exp Ther1992 Jul 01; 262
AB  - L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays. The present study was carried out to characterize the in vivo pharmacology of this potent AII receptor antagonist. In conscious, normotensive and anesthetized pithed rats, L-158,809 inhibits AII (0.1 microgram/kg i.v.) elevations in blood pressure without altering pressor responses to methoxamine or arginine vasopressin. In conscious rats, the relative potencies (ED50) were 29 micrograms/kg i.v. and 23 micrograms/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. In similar experiments using rhesus monkeys, the potencies of L-158,809 were 10 micrograms/kg i.v. and approximately 100 micrograms/kg p.o. In these rats and monkeys, L-158,809 was 10 to 100 times more potent than DuP-753 (losartan) and approximately 3 times more potent than the metabolite, EXP3174. AII-induced elevation of plasma aldosterone in rats was also inhibited by L-158,809. Unlike angiotensin converting enzyme inhibitors, L-158,809 did not potentiate the hypotensive responses to i.v. bradykinin. L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys. The maximum hypotensive responses with acute doses of L-158,809 were equal to those with an angiotensin converting enzyme inhibitor in these renin-dependent animal models. From these in vivo data, L-158,809 is a selective AII receptor antagonist with high potency, good p.o. absorption, long duration and antihypertensive efficacy equal to angiotensin converting enzyme inhibition after single doses.