安定PGI_2誘導体ベラプロストナトリウムの開発

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A novel prostaglandin I_2 (PGI_2) analogue, beraprost sodium, is the first launched drug as an orally active PGI_2. PGI_2 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, PGI_2 is extremely unstable for the use as practical medicines. Thus, stable PGI_2 analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI_2,we started a research on chemically and metabolically stable PGI_2 derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI_2,5,6,7-trinor-4,8-infer-m-phenylenePGI_2 analogues that have the phenol moiety instead of the enolether moiety of PGI_2. Further efforts were devoted to enhance the efficacy of the PGI_2. 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 S_N2' cyclization to prepare cyclopenta [b] benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibited platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug
公益社団法人日本薬学会の論文
1997-08-25

安定PGI_2誘導体ベラプロストナトリウムの開発

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