NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect – why do we keep using it?

Abstract

The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent antiinflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.

RMD86, a thiophene derivative, promotes antinociceptive and antipyretic activities in mice

“…At 25, 50, and 100 mg/kg, RMD86 significantly reduced the number of abdominal contortions. Other studies performed with heterocyclic derivatives have presented similar results in the same test, demonstrating the potential of this group of compounds [17,43].…”

“…In this model, two phases of nociceptive behavior can be observed and seem to involve different stimuli. The first (neurogenic) phase begins immediately after formalin injection, extending for the first 5 min, and results from direct chemical nociceptor stimulation, mainly from C fibers [ 17 ]. The second (inflammatory) phase occurs mainly due to spinal cord stimulation, after sensitization of both nociceptors and central neurons, with release of serotonin, histamine, prostaglandins (PGE2), nitric oxide (NO), excitatory amino acids (glutamate and aspartate), and bradykinin [ 44 , 45 ].…”

“…The ester group at C-3 was maintained, thus maintaining the prodrug characteristic of the new compound. This is also interesting for reducing the typical gastrointestinal effects of classical NSAIDs promoted by the presence of the carboxylic acid group (–COOH), however, without resulting in loss of anti-inflammatory potency [ 17 ].…”

Synthesis, Characterization and Preliminary Anti-inflammatory Evaluation of New Etodolac Derivatives

“…The carboxylic acid group of NSAIDs can be replaced with other groups while these agents still exert a potent anti-inflammatory activity (8) .…”

The Prodrug Approach: A Successful Tool for Improving Drug Solubility

“…The use of NSAID-ester prodrugs is extensively reported in the literature. Controversially, some authors report that the esterification of NSAIDs can reduce the adverse gastric effects by masking the carboxylic acid function; however, the changes in the pharmacokinetic profile that provide sustained release can explain in part the reduced adverse effects seen in some cases [43,44]. In many cases, the lack of solubility limits the use and worsens the adverse effects of NSAIDs.…”