SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF OLIGOETHYLENE ESTER DERIVATIVES AS INDOMETHACIN ORAL PRODRUGS

Five indomethacin oligoethylene ester derivatives (3-7) were synthesiz ed and evaluated for their anti-inflammatory, analgesic, and ulcerogen ic activity after oral administration. The molecular weight of the oli goethylene glycols used far synthesizing esters 3-7 ranged from 106 to 282. The chemical and enzymatic stabilities of esters 3-7 were evalua ted in pH 7.4 and 2.0 buffers and in human plasma, respectively. All t he prodrugs showed a good stability both in pH 7.4 phosphate buffer an d in pH 2.0 buffer, and they were readily hydrolyzed by human plasma. Esters 3-7 showed an anti-inflammatory activity, determined as the per cent inhibition of carrageenan-induced edema, similar to that of indom ethacin, although at higher doses. From writhing test results, we obse rved that all the prodrugs exhibited better or similar analgesic activ ity compared to indomethacin. Esters 3-7 were significantly less irrit ating to the gastric mucosa than indomethacin, after oral administrati on, and esters 3-5 did not show any ulcerogenic activity, although the y were administered at higher doses than indomethacin.