In vivo pharmacologic profile of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors.
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.
Arakida
Y
Y
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Ohga
K
K
Suwa
K
K
Okada
Y
Y
Morio
H
H
Yokota
M
M
Miyata
K
K
Yamada
T
T
Honda
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008297:Male; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D018927:Anti-Asthmatic Agents; D020024:Leukotriene Antagonists; D017482:Receptors, Thromboxane; D013777:Tetrazoles; D013844:Thiazoles; C115704:YM 158; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid