[Thromboxane A2 antagonist--discovery of seratrodast].
We were interested in RCS (rabbit aorta contracting substance) and SRS-A (slow reacting substance of anaphylaxis) and their involvement in human bronchial asthma. When we started our anti-asthmatic drug research in the 1970's. We synthesized a lot of chemical compounds and eventually discovered that AA-861 inhibited the generation of SRS-A from the lung tissue of actively sensitized guinea pigs. AA-861 was found to be a potent 5-lipoxygenase inhibitor. This compound reduced experimental allergic asthma in guinea pigs, but it is easily metabolized in the body. More recently, we found a novel compound, AA-2414 (seratrodast), which is not metabolized in the body. AA-2414 proved to be not a 5-lipoxygenase inhibitor, but a thromboxane A2 (TXA2) receptor antagonist. Seratrodast is the first receptor antagonist that is being developed as an anti-asthmatic drug. Seratrodast inhibits both immediate-, late asthmatic responses in guinea pigs, and also reduces airway hyperresponsiveness in dogs. The anti-asthmatic action of seratrodast in animal models indicates that the drug should be of use in the treatment of human asthmatics. In clinical studies, seratrodast showed a marked effect to improve clinical parameters in bronchial asthma. It is also reported that seratrodast is free from harmful aftereffects. Clinical trials are under way in the US.
Terao
S
S
Pharmaceutical Research Division, Takeda Chemical Industries, Osaka, Japan.
Shiraishi
M
M
Matsumoto
T
T
Ashida
Y
Y
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004285:Dogs; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016859:Lipoxygenase Inhibitors; D008297:Male; D011817:Rabbits; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D018927:Anti-Asthmatic Agents; D016227:Benzoquinones; D006538:Heptanoic Acids; D016859:Lipoxygenase Inhibitors; C060230:seratrodast; D013928:Thromboxane A2; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone