PHARMACOLOGICAL AND PHARMACOKINETIC EVALUATION OF EXP3312, AN ORALLY-ACTIVE NONPEPTIDE ANGIOTENSIN II-RECEPTOR ANTAGONIST

EXP3312, biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde, is a non-p eptide angiotensin II (AII) AT(1)-receptor antagonist. In the rabbit i solated aorta EXP3312 inhibited the contractile response to AII compet itively with a pA(2) 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 fru semide-treated dogs when administered orally at 1 and 3 mg kg(-1). In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 6 0 and 28%, respectively. When EXP3312 was administered intravenously t o 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, -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 pla sma levels of M1 were found in rats after oral administration of EXP33 12, it is likely that M1 contributes to the long duration of the antih ypertensive effects of EXP3312 in renal hypertensive rats.The results show that EXP3312 is a potent, orally active, competitive and selectiv e AT(1)-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.