Seratrodast, a novel benzoquinone derivative, is the first thromboxane A2
(TxA2) receptor antagonist to reach the market. It is orally active for the treatment of
bronchospastic disorders such as asthma. TxA2, a metabolite of the arachidonate
cascade, is involved in several cardiovascular and respiratory diseases through its
potent biological effects on platelet aggregation and constriction of vascular and
respiratory smooth muscles. Seratrodast potently inhibits platelet aggregation and
bronchoconstriction induced by a TxA2 mimic and by a variety of spasmogenic
prostanoids including PGF2α, PGD2 and 9α,11β-PGF2. Seratrodast shows excellent
efficacy in asthma and has been reported to be potentially useful in hyper-responsive
disorder. The R-(+)- seratrodast was reported to be the active isomer.
Thromboxane A2-receptor antagonist. Antiasthmatic.
ChEBI: Seratrodast is an organic molecular entity.
Thromboxane A 2 (TP) receptor antagonist. Antiasthmatic agent; inhibits platelet aggregation and bronchoconstriction induced by a TXA 2 mimetic in guinea pigs.
To toluene (570 mL) was added 2,3,5-trimethylhydroquinone (28.9 g, 0.19 mol) and 7-hydroxy-7-phenylheptanoic acid (42.2 g, 0.19 mol). Boron trifluoride ethyl ether (8.1 g) was added dropwise to the mixture at 60°C for 20 minutes. Stirring of the reaction solution was continued at the same temperature for 2.5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in tetrahydrofuran (300 mL) and oxidation reaction was carried out by adding ferric chloride (102.6 g) and water (300 mL) to convert to quinone compounds. The reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using isopropyl ether as eluent. Finally, the quinone compound was recrystallized from ethanol (250 mL) to give 7-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)-7-phenylheptanoic acid (49.0 g, 73% yield) with a melting point of 128-129 °C.
seratrodast was found to inhibit the aggregation of guinea pig platelets induced by a prostaglandin endoperoxide analogue, u-44069 and the specific binding of another analogue, [3h]u-46619 to washed guinea pig platelets. seratrodast could competitively inhibit the contraction of rabbit aorta and pig coronary arteries induced by u-44069. seratrodast also inhibited the contraction of rabbit aorta induced by pgf2 alpha and the contraction of pig coronary arteries. however, seratrodast had no effect on the antiaggregatory effect of guinea pig platelets [1].
in experiments with guinea pigs, oral seratrodast at 0.1-1 mg/kg could dose-dependently inhibit the platelet aggregation induced by u-44069; the inhibition at 1 mg/kg was 100% at 1 hr and was 89% even at 24 hr after seratrodast administration [1].
7.4 nm for guinea pig platelets
[1] imura, y. ,terashita, z.,shibouta, y., et al. antagonistic action of aa-2414 on thromboxane a2/prostaglandin endoperoxide receptor in platelets and blood vessels. japanese journal of pharmacology 52(1), 35-53 (1990).
