myo-Inositol esters of indomethacin as COX-2 inhibitors.
Carbohydr Res
; 355: 13-8, 2012 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-22578527
ABSTRACT
Ester prodrugs have the potential to eliminate the gastrotoxicity associated with the carboxylic acid group of indomethacin. 4,6-Bis-O-2'-[1'-(4â³-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).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Indometacina
/
Ésteres
/
Ciclo-Oxigenase 2
/
Inibidores de Ciclo-Oxigenase 2
/
Inositol
Limite:
Animals
Idioma:
En
Revista:
Carbohydr Res
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido