The pharmacological profile of BR-A-657, 2- n -butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1 H -tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3 H )-one, a new nonpeptide AT₁-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [¹²⁵I][Sar¹-Ile⁸]angiotensin II (Ang II) from its specific binding sites to AT₁ subtype receptors in membrane fractions of HEK-293 cells with an IC₅₀ of 0.16 n M . In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (p D ′₂: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT₁ receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.