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−chlorobenzenesulfonyl)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.