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

In Vivo Pharmacologic Profile of YM158, a New Dual Antagonist for LeukotrieneﾊD₄ and Thromboxaneﾊ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]-5｢-[3-(4-chlorobenzenesulfonyl)propyl]-2｢-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene (LT)ﾊD₄ and thromboxane (TX)ﾊ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ﾊ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ﾊmg/kg) is greater than that of YM158 (ED₅₀=8.6ﾊ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