Nonpeptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent.
This report describes the pharmacology of (2-n-butyl-4-chloro-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid (EXP3174). EXP3174 is a major metabolite generated after the oral dosing of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H- 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 membranes with an IC50 of 3.7 x 10(-8) M. In the isolated rabbit aorta, EXP3174 caused nonparallel shifts to the right of the AII 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 AII and angiotensin III noncompetitively and did not change the pressor responses to vasopressin 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 AII. 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 AII receptor antagonist and lacks agonistic effect. As EXP3174 is a potent antihypertensive agent, it may be responsible for part of the antihypertensive effect of DuP 753 in rats.
Medical Products Department, E. I. du Pont de Nemours & Company, Wilmington, Delaware.
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Wong
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Price
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Chiu
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Duncia
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Carini
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Wexler
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Johnson
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Timmermans
D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000805:Angiotensin III / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013777:Tetrazoles / Q000378:metabolism* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C066026:losartan carboxylic acid; D019808:Losartan