IN-VITRO PHARMACOLOGICAL PROFILE OF YM158, A NEW DUAL ANTAGONIST FOR LTD4 AND TXA(2) RECEPTORS

YM158 (4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chloro benzenesulfon yl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt mo nohydrate) antagonizes leukotriene (LT) D-4 and thromboxane (TX) A(2) receptors. Functional assays in vitro showed that YM158 exhibits compe titive dual antagonism of LTD4 and TXA(2) receptor-mediated contractio n of isolated guinea pig tracheae, with pA(2) values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD, receptor w as approximately 6.5 times less potent than that of montelukast, and t hat for the TXA(2) receptor was 2.5 times more potent than that of ser atrodast. YM158 also inhibited PGD, and PGF(2 alpha)-induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM 158 antagonized the stable TXA(2) analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced co ntraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA(2) receptors .