Pharmacological and pharmacokinetic evaluation of EXP3312, an orally-active non-peptide angiotensin II-receptor antagonist.
EXP3312, 2-n-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]imidazole-5-carboxylaldehyde, is a non-peptide angiotensin II (AII) AT1-receptor antagonist. In the rabbit isolated aorta EXP3312 inhibited the contractile response to AII competitively with a pA2 value of 8.24. In renal hypertensive rats EXP3312 reduced blood pressure with intravenous and oral ED30 values of 0.19 and 0.14 mg kg-1, respectively. It also reduced blood pressure in frusemide-treated dogs when administered orally at 1 and 3 mg kg-1. In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 60 and 28%, respectively. When EXP3312 was administered intravenously to rats and dogs the plasma elimination half-lives were 1.20 and 2.52 h, respectively. In rats and dogs EXP3312 was metabolized to an active metabolite M1, 2-n-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]imidazole-5-carboxylic acid. M1 is about ten times more potent than EXP3312 in renal hypertensive rats; the intravenous ED30 value was 0.02 mg kg-1. Because high plasma levels of M1 were found in rats after oral administration of EXP3312, it is likely that M1 contributes to the long duration of the antihypertensive effects of EXP3312 in renal hypertensive rats. The results show that EXP3312 is potent, orally active, competitive and selective AT1-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.
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Drug Metabolism and Pharmacokinetics Section, DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA.
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D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006977:Hypertension, Renal / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; C073719:EXP3312