Pharmacological properties of the orally active leukotriene antagonist [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]thio]-1,3,4- thiadiazol-2-yl]thio]acetic acid.
The anti-leukotriene effect of [[5-[[3-(4-acetyl-3-hydroxy -2- propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl] thio] acetic acid (YM-16638) was examined. In isolated guinea-pig ileum, YM-16638 antagonized the contractions induced by slow reacting substance of anaphylaxis (SRS-A) and leukotriene D4 (LTD4) with IC50 values of 6.0 x 10(-8) and 1.1 x 10(-7) mol/l, respectively. However, the compound at 10(-5) mol/l did not affect the contractions induced by histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin (PG)E2 and PGF2 alpha. In isolated guinea-pig trachea, YM-16638 inhibited the contractions elicited by LTC4, LTD4 and LTE4 and its IC50 values were 5.7 x 10(-8), 1.6 x 10(-7) and 9.6 x 10(-8) mol/l, respectively. In isolated human bronchi, YM-16638 also antagonized the contractions induced by LTC4, LTD4 and LTE4 and its IC50 values were 6.0 x 10(-8), 1.2 x 10(-7) and 2.1 x 10(-8) mol/l, respectively. YM-16638 at the doses of 3 to 100 mg/kg p.o. inhibited the skin reaction induced by LTD4 in conscious guinea-pigs and its ED50 value was 17.9 mg/kg p.o. Successive oral administration of YM-16638 (50 mg/kg/d) for 10 days did not develop tolerance in its inhibitory effect against LTD4-induced skin reaction. Furthermore, the compound at the doses of 10 and 30 mg/kg p.o. significantly inhibited the antigen-induced bronchoconstriction in conscious guinea-pigs pretreated with mepyramine, propranolol and indomethacin. These results indicate that YM-16638 is a selective, potent and orally active leukotriene antagonist.
Department of Pharmacology, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
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K
Tomioka
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T
Yamada
T
T
Mase
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H
Hara
K
K
Murase
D000818:Animals; D001249:Asthma / Q000517:prevention & control*; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000633:toxicity; D012882:Skin Tests; D013830:Thiadiazoles / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
D013189:SRS-A; D013830:Thiadiazoles; C056986:YM 16638