Synthesis and Biological Evaluation of Orally Active Prodrugs of Indomethacin

Abstract

Synthesis and biological evaluation of orally active prodrugs (1a-d) of indomethacin are described. Prodrugs 1a-c showed a similar degree of anti-inflammatory activity, and prodrug 1d was found to be less potent than the parent drug indomethacin (1). Ulcer index (UI) data indicated that 1a (UI = 19), 1c (UI = 0), and 1d (UI = 0) were substantially less ulcerogenic and 1b (UI = 62) was more ulcerogenic than parent drug 1 (UI = 47). These prodrugs demonstrated good stability at acidic and basic pH and found to be more lipophilic than parent drug compound 1, indicated by partition coefficients measured in octanol-buffer system at pH 7.4 and 3.0. On the basis of in vivo studies, 1a and 1c compounds were selected for metabolic stability in rat liver microsome (RLM) and rat plasma (RP), and both were found to be enzymatically labile. Prodrugs 1a and 1c emerged as potent anti-inflammatory agents with a lesser potential for ulcer than the parent drug indomethacin.

3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

“…At the same time, it is also one of the most ulcerogenic NSAIDs because of its high COX-1 selectivity and the acidic nature of the drug 12 . From our point of view, there are two main approaches to prevent and/or treat gastroenteropathy associated with indomethacin as an example of traditional NSAIDs; the first comprises synthesis of prodrugs, where a nitric oxide (NO)-donating moiety is covalently attached to NSAID (indomethacin).…”

NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs

“…However, additional factors such as masking of free carboxylic acid group of NSAID as an ester also might be partly contributing to the gastric-sparing effect of these compounds. [29][30][31] Based on its promising oral bioavailability, anti-inflammatory and gastric-sparing properties, we have selected the NOaspirin compound 25 for further evaluation and determined its: A) dose-dependent pharmacokinetics; B) analgesic activity in carrageenan-induced hind paw model of inflammatory pain; C) effect on reducing mucosal prostaglandin E 2 (PGE 2 ) levels via inhibition of cyclooxygenase-1 (COX-1); and D) gastricsparing effects at equal as well as at double the doses and compared the results with those of aspirin at equimolar doses (Fig. 5).…”

The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model

“…Several selective COX-2 inhibitors were introduced for clinical use and displayed remarkable anti-inflammatory properties and reduced gastric toxicity compared with indomethacin; however, severe cardiovascular side effects have been detected after long-term use (Dogne et al, 2005). Recent studies have investigated the use of indomethacin combined with an antioxidant devoid of ulcerogenic side effects, and have shown that the antiinflammatory properties were retained (Bandgar et al, 2011;Bhandari et al, 2010;Doulgkeris et al, 2006). Based on our observations, we suggest that natural antioxidants displaying COX inhibitory activity might serve as promising novel therapeutic agents to treat human patients with lymphedema.…”