Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist.

Summary We examined pharmacological profiles of KT3–671, 2-propyl-8-oxo-l-[(2‘-(lH-tetrazole-5-yl) biphe-nyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole, a newly synthesized nonpeptide angiotensin II (AII) receptor antagonist in various in vitro and in vivo studies. KT3–671 displaced specific binding of [125I]Sar1 Ile8-AII to AT1 receptor with a Ki value of 0.71 ± 0.14 x 10-9M in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10-5M). In isolated rabbit aorta, KT3–671 produced a parallel right-ward shift in the concentration-response curve for AH with a pA2 value of 10.04 ± 0.12, but had no effect on K.CI-, norepinephrine (NE)-, and serotonin (5-HT)-induced contractions. In conscious normotensive rats, KT3–671 (0.3–10 mg/kg, p.o.) inhibited the All-induced pressor response dose dependently. In renal arteryligated hypertensive rats, KT3–671 (0.1–3 mg/kg, p.o.) decreased arterial blood pressure (BP) dose dependently. The hypotensive action of 3 mg/kg KT3–671 was maintained for at least 24 h. These results suggest that KT3–671 is a potent AT1 subtype-selective and competitive nonpeptide AII receptor antagonist and has an orally active antihypertensive effect without agonistic activity.