Synthesis and Pharmacological Evaluation of Some Dual-Acting Amino-alcohol Ester Derivatives of Flurbiprofen and 2-[1,1′-Biphenyl-4-yl]acetic Acid: A Potential Approach to Reduce Local Gastrointestinal Toxicity

Abstract

The search for safer non-steroidal anti-inflammatory drugs (NSAIDs) continues with the failure of anticipated 'ideal' anti-inflammatory agents, the coxibs, on long-term usage. Increased gastric motility and acidity due to the free carboxy group are involved in the etiology of gastric toxicity, common to conventional NSAIDs. Keeping this fact in mind, it was planned to modify some of the conventional NSAIDs to amino-alcohol ester derivatives, which satisfied the structural requirements for these compounds to possess anticholinergic activity in the intact form. Besides blocking the acidic carboxylic group, incorporation of anticholinergic acivity in these molecules was expected to reduce the gastric toxicity by decreasing gastric acid secretion and motility. Synthesis and pharmacological evaluation of six different N,N-disubstituted amino-ethyl ester derivatives, structurally resembling the amino-alcohol ester class of anticholinergic agents, each for [1,1'-biphenyl]-4-acetic acid (3) and flurbiprofen (10), have been reported as potential substitutes for these NSAIDs, with improved therapeutic profile. All the ester derivatives were found to have sufficient chemical stability in buffers (pH 2.0 and 7.4), ensuring them to be absorbed as intact moieties from the gastrointestinal tract. A significant reduction in ulcerogenic potency in comparison to the parent drugs with a slightly higher anti-inflammatory potency suggests that the majority of these candidates have an improved therapeutic profile over their parent drugs. Hence, a promising novel approach, different from the conventional prodrug concept, has been successfully worked out to overcome the local gastric toxicity, yielding therapeutically better compounds for long-term oral anti-inflammatory therapy.

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

“…This result supports previous findings that masking the carboxylic acid moiety of NSAIDs gives safer compounds [5,11]. …”

“…The use of prodrugs is a useful approach to minimize the GIT side effects of NSAIDs [3,5,6,7]. The chemical structures of the prodrug moieties determine the physicochemical properties of the prodrug under development, thus, affect its pharmacological profile.…”

Prodrug Designing of NSAIDs

“…Synthesis of prodrugs of NSAIDs is not only an effective way of overcoming the GI toxicity but could also be used for combining other pharmacological properties or incorporating a chemical moiety for an added beneficial effect (like development of NO-NSAIDs [103,104], conjugation with H 2 receptor antagonist [75] or an analgesic agent [87] and incorporating anticholinergic activity for reducing gastric acid secretion [138][139][140][141][142][143].…”

“…Based on these reports an attempt was made to incorporate anticholinergic activity into the basic molecules of conventional NSAIDs (flurbiprofen, biphenylacetic acid, naproxen, 6-methoxynapthylacetic acid, diclofenac, aspirin and ketorolac) by derivatizing them into N,N-disubstituted aminoalcohol esters. These derivatives were designed specifically to resemble the aminoalcohol ester class of anticholinergics [138][139][140][141][142][143]. An entirely new pharmacodynamic property was incorporated into the original NSAIDs molecules with the anticipation that besides preventing local GI irritation by temporarily blocking carboxyl group present in the NSAIDs, the introduction of anticholinergic activity in the intact esters would further aid in reducing the GI toxicity by (i) decreasing gastric acid secretion and (ii) decreasing gastric motility to maintain optimal mucosal blood flow.…”

Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects

“…Previous studies from our laboratory have revealed that esterification of the carboxylic acid moiety, with different aminoalcohols, in NSAIDs such as flurbiprofen (Halen et al, 2006), naproxen (Halen et al, 2007), and diclofenac (Yadav et al, 2005) generates potent dual acting anticholinergic-antiinflammatory moieties with significantly reduced oral gastric toxicity. The promising results from these candidates prompted us to apply this potential approach to indomethacin (1), a potent indoleacetic acid class of antiinflammatory drug.…”