[Prostaglandins: synthetic and pharmacological studies and development].

The therapeutic use of prostaglandins (PGs) which contain various biological activities and are unstable was successfully achieved. PGs were produced in a large scale according to the Corey method and could be stabilized by the formation of a clathrate compound with cyclodextrin, which enabled the production of marketable form of highly pure PGs. Diligence in the development of native PGs and their structural analogs for human therapy resulted in the following six drugs now being on the market in Japan: PGF2 alpha as the first drug of PGs in the world which induces labor; PGE2 as an orally active labor inducing drug; PGE1 for the treatment of peripheral vascular diseases; gemeprost for therapeutic abortion in the middle-term; ornoprostil, as an oral anti-ulcer agent; limaprost for the treatment of peripheral vascular diseases as an oral agent.

9-Deoxy-delta 9, delta 12-13,14-dihydroprostaglandin D2, a metabolite of prostaglandin D2 formed in human plasma.

Incubation of prostaglandin D2 (PGD2) with human plasma yielded a product that has been identified as 9-deoxy-9,10-didehydro-12,13-didehydro-13,14-dihydro-PGD2 (9-deoxy-delta 9, delta 12-13,14-dihydro-PGD2). The identification was based on mass spectrometry, UV spectrometry, mobilities and retention time on TLC and HPLC, and NMR. The conversion of PGD2 to this product was dependent on the incubation time and the amount of plasma added to a reaction mixture and was abolished by prior boiling. The conversion rate of PGD2 to this metabolite was 0.03 nmol/min per mg of protein of whole plasma at pH 8.0 at 37 degrees C. Similar conversion was also found by incubating PGD2 with human serum albumin added at the concentration found in plasma. These results suggest that the conversion of PGD2 to this product is catalyzed by the enzymatic action of a plasma protein, probably serum albumin. The biological activities of this compound were examined in several systems. It showed negligible activity in inhibition of human platelet aggregation and relaxation of rabbit stomach strip. On the other hand, it exhibited a three times stronger inhibitory activity (IC50, 1.8 microM) than PGD2 (IC50, 5 microM) on the growth of L-1210 cultured cells.

Prostaglandin analogues possessing antinidatory effects. 1. Modification of the omega chain.

Novel prostaglandin analogues modified in the omega chain were prepared by the reaction of the vinyl aldehydes 1a--e with a variety of organometallic reagents as a key step of the syntheses. Compared with the natural prostaglandin F2 alpha in antinidatory effect, the analogues 4, 7, and 10 were 40 times more potent and the analogue 11 was 50--100 times more potent in the rat.

Prostaglandin analogues possessing antinidatory effects. 2. Modification of the alpha chain.

Additional double bonds were introduced into the alpha chain in 16-phenoxy-, 16-(3-chlorophenoxy)-, 16-[3-(tri-fluoromethyl)phenoxy]-, and 16-(4-chlorophenoxy)-17,18,19,20-tetranorprostaglandins which have antinidatory effects. Of these analogues, the delta 3-cis-delta 5 analogues 23b is 1200 times more potent than prostaglandin F2 alpha in antinidatory effect in the rat and more potent than any other known prostaglandin analogues.

An NADP-linked prostaglandin D dehydrogenase in swine brain.

An NADP-linked 15-hydroxyprostaglandin dehydrogenase specific for prostaglandin D2 was discovered and partially purified from cytosol of swine brain. Prostaglandins A2, B2, D3, E2, and F2 alpha were poor substrates for this enzyme, the rates of reaction being less than 10% of that with prostaglandin D2. The enzyme was separated by Sephadex column chromatography from the other NADP-linked 15-hydroxyprostaglandin dehydrogenase that was also present in brain and metabolized prostaglandins B2, E2, and F2 alpha much more effectively than D2. The primary reaction product was tentatively identified as 15-ketoprostaglandin D2 by its characteristic absorption spectrum with a peak at 415 nm at pH 9. This compound was further converted to 13,14-dihydro-15-ketoprostaglandin D2 in the presence of NADPH by the action of 15-ketoprostaglandin delta 13-reductase that was co-purified with the dehydrogenase. This dehydrogenase appears to be responsible for the specific inactivation of prostaglandin D2 which is the major prostaglandin in the central nervous system.