Synthesis and pharmacological evaluation of oligoethylene ester derivatives as indomethacin oral prodrugs.
Five indomethacin oligoethylene ester derivatives (3-7) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity after oral administration. The molecular weight of the oligoethylene glycols used for synthesizing esters 3-7 ranged from 106 to 282. The chemical and enzymatic stabilities of esters 3-7 were evaluated in pH 7.4 and 2.0 buffers and in human plasma, respectively. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by human plasma. Esters 3-7 showed an anti-inflammatory activity, determined as the percent inhibition of carrageenan-induced edema, similar to that of indomethacin, although at higher doses. From writhing test results, we observed that all the prodrugs exhibited better or similar analgesic activity compared to indomethacin. Esters 3-7 were significantly less irritating to the gastric mucosa than indomethacin, after oral administration, and esters 3-5 did not show any ulcerogenic activity, although they were administered at higher doses than indomethacin.
De Caprariis
P
P
Dipartimento di Chimica Farmaceutica e Tossicologica, Facoltà di Farmacia, Università di Napoli Federico II-Via Domenico Montesano, Italy.
Palagiano
F
F
Bonina
F
F
Montenegro
L
L
D'Amico
M
M
Rossi
F
F
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002351:Carrageenan; D002851:Chromatography, High Pressure Liquid; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004952:Esters / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D011355:Prodrugs; D002351:Carrageenan; D007213:Indomethacin