NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS .11. PHARMACOLOGY OF EXP3174 - AN ACTIVE METABOLITE OF DUP753, AN ORALLY ACTIVE ANTIHYPERTENSIVE AGENT

  • 1 October 1990
    • journal article
    • research article
    • Vol. 255  (1) , 211-217
Abstract
This report describes the pharmacology of (2-n-butyl-4-chloro-1-[(2''-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]midazole-5-carboxylic acid (EXP3174). EXP3174 is a major metabolite generated after the oral dosing of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2''-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt in rats. It displaced [3H]angiotensin II (AII) from its specific binding sites in rat adrenal cortical membrane with an IC50 of 3.7 .times. 10-8 M. In the isolated rabbit aorta, EXP3174 caused nonparallel shifts to the right of the All concentration-contractile response curves and reduced the maximal response by 30 to 40% with an apparent pA2 value of 10.09 and a KB value of 10-10 M. At 10-6 M, EXP3174 did not alter the contractile responses to norepinephrine and KCl. In the spinal pithed rat, EXP3174 at 0.03 to 0.3 mg/kg i.v., also inhibited the pressor responses to All and angiotensin III noncompetitively and did not change the pressor responses to vasopressing and norepinephrine. When given i.v. and cumulatively to normotensive rats at 0.003 to 0.3 mg/kg, EXP3174 did not alter blood pressure but inhibited the pressor response to All. In conscious renal artery-ligated rats, EXP3174 decreased blood pressure with an i.v. ED30 of 0.038 mg/kg and a p.o. ED30 of 0.66 mg/kg. These results demonstrate that EXP3174 is a selective and noncompetitive. All receptor antagonist and lacks agonist effect. As EXP3174 is a potent antihypertensive agent, it may be responsible for part of the antihypertensive effect of DuP 753 in rats.