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Vol. 287, Issue 2, 633-639, November 1998

In Vitro Pharmacologic Profile of YM158, a New Dual Antagonist for LTD4 and TXA2 receptors

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

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

YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesulfonyl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D4 and thromboxane (TX) A2 receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD4 and TXA2 receptor-mediated contraction of isolated guinea pig tracheae, with pA2 values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD4 receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA2 receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD2- and PGF2alpha -induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA2 analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA2 receptors.

0022-3565/98/2872-0633$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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[Abstract] [Full Text]


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