Pharmacological Characterization of BR-A-657, a Highly Potent Nonpeptide Angiotensin II Receptor Antagonist

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  • Chi Yong Ha
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Lee Joo Han
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Kim Je Hak
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Tan Hyun Kwang
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Kim Sang Lin
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Lee Jae Yeol
    Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
  • Rim Hong-Kun
    Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University
  • Paik Soo Heui
    Central Research Institute, Boryung Pharm. Co., Ltd.
  • Lee Kyung-Tae
    Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University

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The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-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 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD′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.

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