Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects

Abstract

Synthesis and evaluation of five different N,N-disubstituted aminoethanol ester derivatives of indomethacin bearing structural resemblance to the aminoethanol ester class of anticholinergics are reported herein. The anticholinergic activity was incorporated into the intact esters to overcome the gastric toxicity of indomethacin, not only by blocking the acidic functionality but also by decreasing gastric secretions and motility. These derivatives exhibited in vitro stability in buffers of pH 2.0 and 7.4 for 6 h and were readily hydrolyzed by human plasma esterases to liberate the parent drug. All the derivatives were significantly less irritating to the gastric mucosa than the parent drug. Though only two esters showed antiinflammatory activity similar to that of the parent drug at equivalent dose levels, all the esters were equipotent to indomethacin in the mouse acetic acid-induced writhing assay for analgesic action. The present evaluation indicates that the combined pharmacological properties of these ester derivatives may prove useful for design and development of novel gastric sparing antiinflammatory molecules with potentially important therapeutic applications.

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.…”

Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

“…These effects were the driving force behind the design and synthesis of NSAID prodrugs with non-selective anticholinergic action. These prodrugs were intentionally designed to possess local intrinsic anticholinergic pharmacological activity in the GIT before absorption [71,73,74]. By contrast, NSAID prodrugs with acetylcholinesterase inhibitory activity (AChEI-NSAIDs) are intentionally designed as drugs that can alleviate the inflammatory effect of blistering agents, such as sulfur mustard (2,2′-dichloroethyl sulfide, SM) [75,76].…”

“…There have been a few examples of these NSAID prodrugs in the literature [71,73,74]. In this regard, aminoethyl esters of ketoprofen 21a – f , flurbiprofen 22a – 22f and indomethacin 23a – e incorporating open and cyclic amines were synthesized and evaluated (Figure 18 and Table 2).…”

“…Most of the esters released 17.9%–79.9% of the parent NSAID in human plasma after 2 h and were demonstrated to be competitive reversible antagonists with pA 2 values ≤7.58 compared to 8.20 for atropine sulfate [71,73,74]. pA 2 reflects the affinity of atropine for its receptor and is defined as “the negative logarithm of the molar concentration of an equilibrium competitive antagonist, which reduces the effect of a double concentration of agonist to that of a single one” [78].…”