Jpn. J. Pharmacol. 83 (1), 63-72 (2000)


In Vivo Pharmacologic Profile of YM158, a New Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors

Yasuhito Arakida, Keiko Ohga, Kiyomi Suwa, Yohei Okada, Hiroki Morio, Masaki Yokota, Keiji Miyata, Toshimitsu Yamada and Kazuo Honda


Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,
21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan

Abstract: The antagonistic activity of oral YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5Ę-[3-(4-chlorobenzenesulfonyl)propyl]-2Ę-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene (LT) D4 and thromboxane (TX) A2 receptors, was investigated. Oral YM158 caused dose-dependent inhibition of LTD4-induced increases in plasma leakage and LTD4- or U46619-induced increases in airway resistance, with ED50 values of 6.6, 8.6 and 14 mg/kg, respectively. The dose-range of YM158's inhibitions was almost the same for both LTD4 and TXA2 receptors, and repeated oral doses did not affect its efficacy. Furthermore, oral YM158 inhibited antigen-induced bronchoconstriction. Although the potency of pranlukast for LTD4 receptor antagonism (ED50=0.34 mg/kg) is greater than that of YM158 (ED50=8.6 mg/kg), the doses of both pranlukast and YM158 for significant inhibition of the antigen-evoked airway response were the same, indicating that the TXA2 receptor antagonism of YM158 plays an important role in its anti-asthmatic effects. In conclusion, YM158 promises to be a novel agent for treating bronchial asthma.

Keywords: YM158, Leukotriene D4, Thromboxane A2, Receptor antagonist, Asthma


Copyright© The Japanese Pharmacological Society 2000

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