Structure-activity relationship (SAR) among prostacyclin (PGI2) analogues.

The main aims of the research for new PGI2 analogues are to increase (1) the duration of action and/or (2) biological selectivity. To meet requirement (1), the structure of PGI2 had to be stabilized chemically and biologically. To achieve chemical stabilization an electron-withdrawing group (e.g. oxo-, phenyl) was inserted adjacent to the enol-ether unit into the PGI2 molecule. Such compounds as 7-oxo-PGI2, 4-oxo-PGI2, m-interphenylene-2,3,4-trinor-PGI2 are stable to hydrolysis although they possess a somewhat diminished biological activity as measured by the antiaggregatory activity and in vivo hypotensive action. There was no significant change in the selectivity between the two kinds of activities. "Biological stabilization" was attempted by elaborating the series of m-interphenylene-PGI2-s with modification of the PG-skeleton. Compounds such as m-interphenylene-2,3,4-trinor-13,14-didehidro-20-methy l-PGI2 is considered to be "fully stabilized". There was a gain in selectivity, however the increase in the duration of action was not significant. However, even PGI2 has certain activities of the "hit and run" type revealed mainly in the cytoprotective effect at different organs. Such an example, the delayed antiischaemic effects of PGI2 and 7-oxo-PGI2 in dogs are discussed.