title: 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 24h at 37°C and showed comparable activity to indomethacin in a COX-2 assay (pH 8.0).
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Kadirvel
authors.forename: Amna Salem
authors.initials: AS
authors.lastname: Abudalal
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajendran
authors.forename: Abdul
authors.initials: A
authors.lastname: Gbaj
authors.forename: Constantinos
authors.initials: C
authors.lastname: Demonacos
authors.forename: Sally
authors.initials: S
authors.lastname: Freeman
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007294:Inositol / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D007294:Inositol; D051546:Cyclooxygenase 2; D007213:Indomethacin