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).
Bibliographical noteFunding Information:
We thank Devi Kadirvel for the generous gift of Etoricoxib, and Anand Patel and Usman Shabbir for technical assistance. M.K. is grateful for support from an Overseas Research Scholarship and the University of Manchester.
ASJC Scopus subject areas
- Analytical Chemistry
- Organic Chemistry