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). © 2012 Elsevier Ltd. All rights reserved.