Terashita Z, Imura Y, Tanabe M, Kawazoe K, Nishikawa K, Kato K, Terao S
Thromb Res. 1986 Jan 15;41(2):223-37. doi: 10.1016/0049-3848(86)90231-8.
(E)-7-Phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151) inhibited horse platelet microsomal thromboxane (TX) A2 synthetase with an IC50 of 2.6 X 10(-8) M, but even at a high concentration of 10(-4) M it had little effect on cyclooxygenase, PGI2 synthetase and 5-lipoxygenase in in vitro enzymatic assays. CV-4151 did not affect PGI2 release from rat and rabbit aortic tissues in in vitro (10(-4) M) and ex vivo (10 and 100 mg/kg, p.o.) experiments, whereas aspirin (10(-4) M or 10 and 100 mg/kg, p.o.) markedly inhibited PGI2 release in these preparations. When given orally to rats and dogs, CV-4151 markedly inhibited blood TXA2 synthetase activity: the ID50 values (mg/kg, 2 hr later) were 0.05 in rats and 0.17 in dogs. The inhibitory effects at an oral dose of 1 mg/kg lasted more than 24 hr in both species; the inhibition was 41% in rats and 32% in dogs 24 hr after the administration. When injected i.v. to rats and dogs, CV-4151 caused inhibitory effects on TXA2 synthetase equipotent to those observed with the oral administration. In both species, CV-4151 given orally increased concentration of serum immunoreactive 6-keto-PGF1 alpha concomitant with a decrease of serum TXB2-8 concentration. CV-4151 was equipotent to OKY-1580 (IC50: 2.3 X 10 M), a well documented TXA2 synthetase inhibitor, in an in vitro TXA2 synthetase assay. However, CV-4151, given orally or i.v. to rats and dogs, was much more potent and longer acting in inhibition of blood TXA2 production than OKY-1580. Dazoxiben was less potent than these compounds in vitro. In rats, serial oral administration of CV-4151 (10 mg/kg) once daily for 14 days produced a constant and marked reduction of serum TXB2 concentration with concomitant increase of serum immunoreactive 6-keto-PGF1 alpha concentration. No rebound phenomenon in inhibition of TXA2 synthetase was observed after the dosing was stopped. These findings indicate that CV-4151 is a potent and long acting selective inhibitor of TXA2 synthetase and may reorient the metabolism of PG endoperoxides to PGI2.
（E）-7-苯基-7-（3-吡啶基）-6-庚烯酸（CV-4151）抑制马血小板微粒体血栓素（TX）A2合成酶，IC50为2.6×10^(-8)M，但即使在10^(-4)M的高浓度下，在体外酶促试验中对环氧化酶、前列环素（PGI2）合成酶和5-脂氧合酶的影响也很小。在体外（10^(-4)M）和离体（10和100mg/kg，口服）实验中，CV-4151不影响大鼠和兔主动脉组织中PGI2的释放，而阿司匹林（10^(-4)M或10和100mg/kg，口服）在这些制剂中显著抑制PGI2的释放。给大鼠和狗口服CV-4151可显著抑制血液中TXA2合成酶活性：ID50值（mg/kg，2小时后）在大鼠中为0.05，在狗中为0.17。在两个物种中，口服1mg/kg剂量的抑制作用持续超过24小时；给药后24小时，大鼠的抑制率为41%，狗的抑制率为32%。当给大鼠和狗静脉注射时，CV-4151对TXA2合成酶的抑制作用与口服给药时观察到的相当。在两个物种中，口服CV-4151会使血清免疫反应性6-酮-PGF1α浓度升高，同时血清TXB2-8浓度降低。在体外TXA2合成酶试验中，CV-4151与已充分记录的TXA2合成酶抑制剂OKY-1580（IC50：2.3×10^(-8)M）等效。然而，给大鼠和狗口服或静脉注射CV-4151在抑制血液中TXA2产生方面比OKY-1580更有效且作用时间更长。达唑氧苯在体外的效力低于这些化合物。在大鼠中，连续14天每天口服一次CV-4151（10mg/kg）可使血清TXB2浓度持续显著降低，同时血清免疫反应性6-酮-PGF1α浓度升高。停药后未观察到TXA2合成酶抑制的反弹现象。这些发现表明CV-4151是一种强效且长效的TXA2合成酶选择性抑制剂，可能使PG内过氧化物的代谢重新导向为PGI2。
