myo-Inositol esters of indomethacin as COX-2 inhibitors

Ester prodrugs have the potential to eliminate the gastrotoxicity associated with the carboxylic acid group of indomethacin. 4,6-Bis-O-2′-[1′-(4″-chlorobenzoyl)-5′-methoxy-2′-methyl-1′H-indol-3′-acetyl]-myo-inositol-1,3,5-orthoacetate (2) was synthesised and evaluated as a COX-2 inhibitor. It adopts a conformationally restricted chair with two indomethacin groups in the sterically hindered 1,3-diaxial positions. Acid-induced cleavage of the orthoacetate lock of the prodrug leads to a ring flip of the myo-inositol ring with the two indomethacin groups now in 1,3-diequatorial positions. This increases the susceptibility of hydrolysis of the ester groups to release indomethacin under acidic conditions. The long half-life (152 min) of decomposition of (2) at ∼pH 1–2 suggests that it may bypass the stomach with minimal hydrolysis upon oral administration. Indomethacin ester (2) was completely stable at pH 4.0–8.5 over 24 h at 37 °C and showed comparable activity to indomethacin in a COX-2 assay (pH 8.0).

Graphical abstractCompound (2) was synthesised and evaluated as a COX-2 inhibitor. Acid-induced hydrolysis of the orthoacetate lock gives (7eq) in a pentaequatorial conformation, which undergoes hydrolysis to release indomethacin.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel compounds (1) and (2) were synthesised as myo-inositol esters of indomethacin. ► Hydrolysis studies monitoring the release of indomethacin have been reported. ► The indomethacin ester (2), showed comparable activity in a COX-2 assay.