Jpn. J. Pharmacol. 81 (1), 21 - 28 (1999)


ATZ1993, an Orally Active and Novel Nonpeptide Antagonist for Endothelin Receptors and Inhibition of Intimal Hyperplasia After Balloon Denudation of the Rabbit Carotid Artery

Hiroshi Azuma1, Jun Sato1, Hiroshi Masuda1, Moritaka Goto1, Satoru Tamaoki1, Akiko Sugimoto1, Hidehisa Hamasaki2 and Haruo Yamashita2

1Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University, 2 - 3 - 10 Surugadai, Kanda, Chiyoda-ku, Tokyo 101 - 0062, Japan
2Pharmacology and Organic Chemistry Research Departments, Teikoku Hormone MFG., 1604 Shimo-Sakunobe, Takatsu-ku, Kawasaki 213 - 8522, Japan

Abstract: The present experiments were designed to investigate the effect of ATZ1993 o3-carboxy-4,5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)methoxy-[1H]-benz[g]indazolep on the intimal hyperplasia after balloon endothelial denudation of the rabbit carotid artery. ATZ1993 inhibited the specific [125I]endothelin (ET)-1 binding not only to ET-receptor subtype A (ETA) with a pKi value of 8.69}0.02, but also to ET-receptor subtype B (ETB) with a pKi value of 7.20}0.03. Counterscreening in the binding assay (30 different receptors) confirmed that ATZ1993 had a high selectivity for ET receptors. Increases in intima:media ratio and DNA content in the vessel wall were significantly (P<0.005) inhibited by ATZ1993 in a daily dose of 30 mgE200 ml-1Ekg-1 for 1 week before and 6 weeks after balloon denudation. Inhibition of the intimal hyperplasia with ATZ1993 was determined as approximately 77% for increases in intima:media ratio and DNA content. Plasma concentrations of ATZ1993 ranged between 121.6}26.6 and 131.7}20.9 nM throughout experimental periods. Mean arterial blood pressure, heart rate and body weight gain remained unaffected by administering ATZ1993. These results demonstrate that ATZ1993 is a novel nonpeptide and nonselective ETA/ETB-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.

Keywords: ATZ1993, Novel endothelin receptor antagonist, Inhibition of intimal hyperplasia, Balloon endothelial denudation, Rabbit carotid artery


CopyrightŠ The Japanese Pharmacological Society 1999

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