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In vivo pharmacologic profile of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors.

Abstract
The antagonistic activity of oral YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl)propyl]-2'-(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.
AuthorsY Arakida, K Ohga, K Suwa, Y Okada, H Morio, M Yokota, K Miyata, T Yamada, K Honda
JournalJapanese journal of pharmacology (Jpn J Pharmacol) Vol. 83 Issue 1 Pg. 63-72 (May 2000) ISSN: 0021-5198 [Print] Japan
PMID10887942 (Publication Type: Journal Article)
Chemical References
  • Anti-Asthmatic Agents
  • Leukotriene Antagonists
  • Receptors, Thromboxane
  • Tetrazoles
  • Thiazoles
  • YM 158
  • Leukotriene D4
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Topics
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (antagonists & inhibitors)
  • Airway Resistance (drug effects)
  • Animals
  • Anti-Asthmatic Agents (pharmacology)
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Leukotriene Antagonists (pharmacology)
  • Leukotriene D4 (antagonists & inhibitors)
  • Male
  • Receptors, Thromboxane (antagonists & inhibitors)
  • Tetrazoles (pharmacology)
  • Thiazoles (pharmacology)

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