Nishio S, Nagase H, Kanou K, Aoki S, Kanbayashi Y
Basic Research Laboratories, Toray Industries, Inc., Kanagawa, Japan.
Yakugaku Zasshi. 1997 Aug;117(8):509-21. doi: 10.1248/yakushi1947.117.8_509.
A novel prostaglandin I2 (PGI2) analogue, beraprost sodium, is the first launched drug as an orally active PGI2. PGI2 was discovered in 1976, and has attracted much attention as a medicine for cardiovascular diseases such as strokes and heart attacks because of its potent antiplatelet and vasodilating effect. However, PGI2 is extremely unstable for the use as practical medicines. Thus, stable PGI2 analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI2, we started a research on chemically and metabolically stable PGI2 derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI2, 5,6,7-trinor-4,8-inter-m-phenylenePGI2 analogues that have the phenol moiety instead of the enolether moiety of PGI2. Further efforts were devoted to enhance the efficacy of the PGI2 analogues and to eliminate their side effects, and an orally active analogue, beraprost sodium, was obtained. In order to establish the synthetic route of beraprost sodium, various novel processes were invented, including ortho-selective metalation of bromoanisoles by means of Grignard reagents, copper-catalyzed SN2' cyclization to prepare cyclopenta[b]benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibit platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug has a potent antiplatelet effect both in vitro and ex vivo in human and several animal species. In clinical studies, beraprost sodium exerted a marked effect to improve arteriosclerosis obliterans. No serious adverse effects related with the drug have been reported. It was highly evaluated as an orally active PGI2 by pharmaceutical companies overseas as well, and now clinical trials are under way in U.S.A. and Europe.
一种新型前列腺素I2（PGI2）类似物贝前列素钠，是首个作为口服活性PGI2推出的药物。PGI2于1976年被发现，因其强大的抗血小板和血管舒张作用，作为治疗中风和心脏病等心血管疾病的药物备受关注。然而，PGI2作为实用药物极不稳定。因此，世界各地的众多研究人员都在探索稳定的PGI2类似物。在PGI2被发现后不久，我们就开始研究化学和代谢稳定、作用持续时间更长且不良反应更少的PGI2衍生物。我们发明了一类新型稳定的PGI2，即5,6,7-三降-4,8-间-亚苯基PGI2类似物，其具有酚基部分而非PGI2的烯醚基部分。我们进一步努力提高PGI2类似物的疗效并消除其副作用，从而获得了口服活性类似物贝前列素钠。为了确立贝前列素钠的合成路线，发明了各种新颖的方法，包括通过格氏试剂对溴代苯甲醚进行邻位选择性金属化、铜催化的SN2'环化反应制备环戊并[b]苯并呋喃，以及通过普林斯反应对ω-侧链进行立体选择性延长。贝前列素钠可抑制由腺苷5'-二磷酸（ADP）、胶原蛋白和花生四烯酸诱导的血小板聚集。结果表明，该药物在体外和体内对人和多种动物物种均具有强大的抗血小板作用。在临床研究中，贝前列素钠对改善闭塞性动脉硬化症有显著效果。尚未报告与该药物相关的严重不良反应。它也受到了海外制药公司的高度评价，被视为口服活性PGI2，目前美国和欧洲正在进行临床试验。
