Thromboxane A2 Antagonist : Discovery of Seratrodast

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  • トロンボキサンA2受容体拮抗薬 : セラトロダストの創製研究
  • トロンボキサン A2 ジュヨウタイ キッコウヤク セラトロダスト ノ ソウセイ ケンキュウ

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Abstract

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.

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 119 (5), 377-390, 1999

    The Pharmaceutical Society of Japan

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