myo-Inositol esters of indomethacin as COX-2 inhibitors

Abstract 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).