Structure-Activity Studies of 16-Methoxy-16-methyl Prostaglandins

Article abstract of DOI:10.1021/jm00160a005

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF_2α, -PGE₂, and PGE₁ is described.The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra.The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects.Both the C-15 and C-16 configurations were found to be critical for the biological activities.These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action.One of the PGE₁ derivatives, 9f(15α,16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.