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

  1. Yasuhito Arakida,
  2. Kiyomi Suwa,
  3. Keiko Ohga,
  4. Masaki Yokota,
  5. Keiji Miyata,
  6. Toshimitsu Yamada and
  7. Kazuo Honda
  1. Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan

    Abstract

    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 PGF2α-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.

    Footnotes

    • Send reprint requests to: Yasuhito Arakida, Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.

    • Abbreviations:
      LT
      leukotriene
      Cys-LTs
      cysteinyl-leukotrienes (LTC4, LTD4 and LTE4)
      TX
      thromboxane
      PG
      prostaglandin
      PRP
      platelet-rich plasma
      PPP
      platelet-poor plasma
      IC50
      concentration causing 50% inhibition
      EC50
      concentration causing 50% effect
      YM158
      (3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate)
      • Received January 7, 1998.
      • Accepted June 17, 1998.
    « Previous | Next Article »Table of Contents

    This Article

    1. JPET November 1, 1998 vol. 287 no. 2 633-639
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 331 (2)
    1. Current Issue
    1. Alert me to new issues of JPET