Synthesis, Characterization, and Biological Evaluation of Novel Diclofenac Prodrugs

Abstract

Diclofenac ester pro drugs (4, 5, 6) were synthesized and evaluated in vitro and in vivo for their potential use for oral delivery, with the aim of obtaining enzymatically labile and less ulceration drugs than the parent drug diclofenac sodium (1a). Prodrugs 4, 5, 6 were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium. Prodrugs 4, 5, 6 rapidly underwent enzymatic hydrolysis to release the parent drug diclofenac in 30-60 min in rat liver microsomes (RLM) and rat plasma (RP). Prodrugs were found to be more lipophilic when the partition coefficient was measured in 1-octanol and buffer system at pH 7.4 and 3.0. Diclofenac prodrugs 4, 5, 6 were found to be crystalline in nature (analyzed by PXRD). Prodrug 4 was found to be a superior candidate for the treatment of chronic inflammatory diseases.

Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

“…The authors’ synthesized esters prodrugs of diclofenac was less ulcerogenic and with 2000-fold increase in solubility over diclofenac [21]. Another study described the synthesis of diclofenac prodrugs as more lipophilic than parental drug with reduced gastro-ulcerogenic effects [22]. We have previously described that masking acid function of diclofenac into lactam derivatives could provide compounds with anti-inflammatory activity with the same nonulcerogenic properties.…”

Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

“…For example, 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without GI ulceration effect [11,12]. Diclofenac ester prodrugs were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium [13,14,15,16,17]. Additionally, Conjugation of diclofenac with 2-hydroxylethylmethacrylate resulted in a monomeric drug derivative of diclofenac that possesses lower ulcergenic properties than the parent drug [18].…”

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).…”