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.