In vivo pharmacologic profile of YM158, a new dual antagonist for leukotriene D-4 and thromboxane A(2) receptors

The antagonistic activity of oral YM158 (3-[(4-tert-butylthiazol-2-yl)metho xy]-5'-[3-(4-chlorobenzenesulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benz anilide monosodium salt monohydrate), a new dual antagonist for leukotriene (LT) D-4 and thromboxane (TX) A(2) receptors, was investigated. Oral YM158 caused dose-dependent inhibition of LTD4-induced increases in plasma leaka ge and LTD4- or U46619-induced increases in airway resistance, with ED50 va lues of 6.6, 8.6 and 14 mg/kg, respectively. The dose-range of YM158's inhi bitions was almost the same for both LTD4 and TXA(2) receptors, and repeate d oral doses did not affect its efficacy. Furthermore, oral YM158 inhibited antigen-induced bronchoconstriction. Although the potency of pranlukast fo r LTD4 receptor antagonism (ED50 = 0.34 mg/kg) is greater than that of YM15 8 (ED50 = 8.6 mg/kg), the doses of both pranlukast and YM158 for significan t inhibition of the antigen-evoked airway response were the same, indicatin g that the TXA(2) receptor antagonism of YM158 plays an important role in i ts anti-asthmatic effects. In conclusion, YM158 promises to be a novel agen t for treating bronchial asthma.