Prodrugs Of Non-steroidal Anti-inflammatory Drugs Research Articles

Development, Characterization and Pharmacological Investigation of Umbelliferone Conjugates of NSAIDs

The present investigation developed the ester prodrugs of Non-steroidal anti inflammatory drugs (NSAIDs), Mefenamic acid and Flurbiprofen by conjugating with the natural antioxidant, 4-methyl umbelliferone that resulted the formation of Mefenamic acid-umbelliferone ester prodrug and Flurbiprofen-umbelliferone ester prodrug .The principal objective this study is the synthesis of the ester prodrugs of NSAIDs with the enhanced therapeutic activity and minimized side effects. Prodrugs were synthesized by coupling method using N,N’- dicyclohexylcarbodiimide/4-dimethylaminopyrimidine, subjected to physical, chemical characterization, spectral characterization (IR, 1H NMR, 13C NMR and Mass spectra),hydrolysis-kinetic study and pharmacological evaluation such as anti-inflammatory, ulcerogenecity as well as the effect of the NSAIDs in the central nervous system against degenerative mechanisms. The current study revealed that the umbelliferone conjugates of NSAIDs which upon administration would release the parent drug as a result of enzymatic or non-enzymatic hydrolysis in the desired site with enhanced anti inflammatory activity and reduction in the gastro intestinal toxicity. Also the synthesized pordrugs showed enhanced brain targeting efficiency with protective action against the degenerative processes.

Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse, and human of 3.44-141 min, 2.51-14 min, 0.58-1.31 min, and 0.23-1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6- to 28-fold larger than in plasma. The results highlight the significance of species and tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

Prodrugs of Non-steroidal Anti-inflammatory Drugs (NSAIDs): A Long March Towards Synthesis of Safer NSAIDs.

As a therapeutic group, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used, prescribed and over the counter (OTC) medications for the treatment of inflammatory diseases, but suffering from several undesired side effects, the most important being ulcerogenicity, mucosal hemorrhage and gastritis. Most of the NSAID moieties are chemically composed of carboxylic functional groups and this could be one of the reasons for the damage to the mucosal lining. The prodrug designing is one of the several strategies used to overcome this drawback. Hence, in the last decade, the design and the synthesis of prodrugs of NSAIDs have been explored and given much attention by medicinal chemists. The rationale behind the prodrug concept is to achieve temporary blockade of the free carboxylic group present in the NSAIDs till their systemic absorption. This review is aimed to highlight and provide important information on NSAID prodrugs that have been designed and reported to be safe and more effective. This review will also focus on NSAID prodrugs that have been designed for improving therapeutic i.e. anti-inflammatory action as well as improving drug delivery at the target site. The most common derivatives of carboxylic NSAIDs that are discussed here belong to the chemical classes of esters, amides, anhydrides, acetals and the other derivatives with completely masked carboxylic groups. The successful prodrugs were listed and their molecular structures were also demonstrated here. The present review covers the recent updates present in literature and will surely provide a greater insight into the designing of safer NSAIDs in the future.

Preparation and Characterization of Polymeric Prodrugs of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) by Cold Plasma Technique

A methacrylic-type polymerizable derivative of naproxen (NP), planned as a prodrug, was directly synthesized from the reaction between 2-hydroxyethyl methacrylate (HEMA) and NP by the esterification method. Then, the polymeric prodrugs containing NP pendent groups were synthesized by the free radical polymerization on plasma irradiated pharmaceutical excipient powders. Hydrolysis of the polymeric prodrugs was carried out in conditions similar to physiological conditions and the results showed that the studied polymeric prodrugs in the present investigation can be used as carriers in controlled drug release, to meet the need for prolonged and better control of drug administration.

Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases

It has been reported that delivery systems based on dendritic prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) improved the properties of drug molecules and reduced the side effects and irritation on the gastric mucosa. To find a more effective way in NSAIDs dendritic prodrugs, in this paper, three different dendritic scaffolds of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. These self-immolative dendritic NISADs prodrugs programmed to release multiple molecules of the potent naproxen after a single enzymatic activation step, and in 50% human plasma, the drug released from the compound T3 reaching 47.3% after 24h in vitro assay. Moreover, all prodrugs were also found to maintain more significant anti-inflammatory activity, no significant cytotoxicity against HEK293 cells and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen. These results provided an effective entry to the development of new dendritic NSAIDs prodrugs.

Lipase‐catalyzed synthesis of polymeric prodrugs of nonsteroidal anti‐inflammatory drugs

AbstractBecause of the potential application of prodrugs of nonsteroidal anti‐inflammatory drugs (NSAIDs), Candida antarctica lipase B (CAL‐B) catalyzed polycondensation of profen‐containing diol monomers and diesters were designed to prepare a series of biodegradable polymeric prodrugs composed of NSAID branches and poly(amide‐co‐ester) backbone. The structure of the products was confirmed by Fourier transform infrared spectroscopy, NMR, and gel permeation chromatography (GPC). The reaction conditions of polymerization, such as the enzyme source, amount of catalyst, and temperature, were optimized. The molecular weights of resultant copolymers were 2170–13,270 g/mol, with corresponding polydispersities from 1.17 to 2.4. The copolymers had relatively high drug loadings of 44.7–59.7 wt % because every repeat unit contained one drug molecule. The strategy of enzymatic polymerization appeared to be quite general and accommodated a large number of comonomer substrates with various chain lengths and substituents. The optically pure (R)‐naproxen monomer was demonstratively incorporated into the corresponding copolymers with the developed synthesis strategy. The in vitro study showed that the polyester could release the drug effectively under physiological conditions with enzyme, which indicated that the obtained product could be a promising prodrug for extending pharmacological effects by delayed drug release. With GPC analysis, we confirmed that the prodrug was completely degradable in aqueous solution. The attractive features of the copolymer were its high drug loading, biodegradability, and biocompatibility. The high tolerance of the CAL‐B toward drug groups, as described in this article, provides a new route for synthesizing polymeric drugs with potential biomedical applications in mild conditions and for reducing environmental impact. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

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

In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E(2) (PGE(2)) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.

Ethanesulfohydroxamic Acid Ester Prodrugs of Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Synthesis, Nitric oxide and Nitroxyl Release, Cyclooxygenase Inhibition, Anti-inflammatory, and Ulcerogenicity Index Studies

The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S)-naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH(2)CH(2)SO(2)NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 μmol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO.

ChemInform Abstract: 5-Acyloxy-1,3-dioxolan-4-ones as Prodrugs of Non-Steroidal Antiinflammatory Drugs.

ChemInform Abstract: 5-Acyloxy-1,3-dioxolan-4-ones as Prodrugs of Non-Steroidal Antiinflammatory Drugs.

Low Direct Cytotoxicity of Loxoprofen on Gastric Mucosal Cells

Pro-drugs of non-steroidal anti-inflammatory drugs (NSAIDs), such as loxoprofen are widely used for clinical purposes because they are not so harmful to the gastrointestinal mucosa. We recently showed that NSAIDs such as indomethacin and celecoxib have direct cytotoxicity (ability to induce necrosis and apoptosis in gastric mucosal cells) due to their membrane permeabilizing activities, which is involved in NSAID-induced gastric lesions. We show here that under conditions where indomethacin and celecoxib clearly induce necrosis and apoptosis, loxoprofen and its active metabolite loxoprofen-OH, do not have such effects in primary culture of guinea pig gastric mucosal cells. Loxoprofen and loxoprofen-OH induced apoptosis more effectively in cultured human gastric cancer cells than in the primary culture. Loxoprofen and loxoprofen-OH exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We thus consider that the low direct cytotoxicity of loxoprofen observed in vitro is involved in its relative safety on production of gastric lesions in clinical situation.

Nanoprodrugs of NSAIDs Inhibit the Growth of U87‐MG Glioma Cells

Several recent reports have demonstrated that nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit the growth of various malignant cells suggesting their application as anticancer agents. In this study, we prepared six nanometer‐sized prodrugs (nanoprodrugs) of NSAIDs, ibuprofen, indomethacin, and naproxen through the spontaneous emulsification mechanism using monomeric and dimeric derivatives of the NSAIDs. We evaluated their effect on the proliferation of U87‐MG glioma cells by cell counting, WST‐1 cell proliferation reagent, and propidium iodide incorporation. The two ibuprofen nanoprodrugs inhibited the cell growth more potently than the indomethacin nanoprodrugs, whereas the naproxen nanoprodrugs did not show any significant effect. Remarkably, ibuprofen did not show any effect at an equimolar concentration. Approximately, 4.4% of the ibuprofen nanoprodrugs was found in the cell, whereas no ibuprofen could be detected suggesting that the superior effect of the nanoprodrugs can be attributed to the efficient cellular uptake of the nanoprodrugs.

NO-NSAIDs: Gastric-sparing nitric oxide-releasable prodrugs of non-steroidal anti-inflammatory drugs

Recently, a new class of nitric-oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) is being studied as ‘Safe NSAIDs’ because of their gastric-sparing properties. As an extension of our novel disulfide linker technology, we have designed, synthesized and evaluated novel NO-releasing NSAID prodrugs such as NO-Aspirin ( 1b– d) and NO-Diclofenac ( 2b– c). Although the amide-containing derivative 1d did not show any bioavailability, the remaining compounds have shown fair to excellent pharmacokinetic, anti-inflammatory and gastric-sparing properties. Among them, however, the NO-Diclofenac ( 2b) has shown the most promising pharmacokinetic, anti-inflammatory and NO-releasing properties and protected rats from NSAID-induced gastric damage which could be attributable to the beneficial effects of NO released from these prodrugs.

Stimuli-responsive antioxidant nanoprodrugs of NSAIDs

A novel group of α-lipoic acid-containing hydrophobic prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) was synthesized and transformed into nanometer-sized prodrugs (nanoprodrugs). Three NSAIDs, indomethacin, ibuprofen and naproxen were linked to α-lipoic acid via tetraethylene glycol through hydrolytically degradable ester bonds. The three bifunctional derivatives were dissolved in organic solvents and capable of forming stable nanoprodrugs upon addition of the organic solutions into aqueous phase through the spontaneous emulsification mechanism. Antioxidant property and stimuli-responsiveness of the nanoprodrugs were demonstrated by hypochlorous acid (HOCl) scavenging followed by oxidative destabilization of the nanoprodrugs. The effect of varying NSAIDs on the in vitro hydrolytic prodrug activation catalyzed by porcine liver esterase was investigated by monitoring the rates of NSAIDs hydrolysis from the nanoprodrugs. The remarkable feature of these nanoprodrugs is that despite the highly hydrophobic nature of the derivatives NSAIDs were readily hydrolyzed enzymatically from the nanoprodrugs. Furthermore, the rate of hydrolysis was higher when the nanoprodrugs were oxidized and destabilized upon HOCl scavenging suggesting an enhanced activation of the nanoprodrugs in the oxidative environment.

Low Direct Cytotoxicity of Nabumetone on Gastric Mucosal Cells

Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for clinical purposes because they are not harmful to the gastrointestinal mucosa. We recently showed that NSAIDs have direct cytotoxicity in NSAID-induced gastric lesions. We show here that under conditions where the NSAIDs indomethacin and celecoxib clearly induce cell death, an NSAID prodrug, nabumetone, and its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), did not have such effects. Moreover, nabumetone and 6MNA exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We recently reported that when an orally administered NSAID was used in combination with a low dose of intravenously administered indomethacin, the severity of gastric lesions produced in rats depended on the cytotoxicity of the orally administered NSAID. Using a similar protocol, we show here that gastric lesions were produced when the orally administered NSAID was celecoxib, but not when nabumetone was used. We thus propose that the low direct cytotoxicity of nabumetone observed in vitro is maintained in vivo, and that the use of nabumetone does not harm the gastric mucosa.

Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS

Recently non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to prevent or to cure Alzheimer's disease. In this respect, we synthesized new potential prodrugs of several NSAIDs in order to increase their access to the brain. The carboxylic group of NSAIDs was attached to the 1,4-dihydro-1-methylpyridine-3-carboxylate moiety, which acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. The lipophilicity of potential prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic Rm value, and by predictive computational methods. From experimental parameters, all prodrugs were more lipophilic when compared to their corresponding parent compounds and consequently a better blood brain barrier (BBB) penetration is hypothesised. Prodrug lipophilicity was correlated with a calculated log P value according to Kowwin's method. The correlation between experimental Rm0 and calculated log P, determined by PLS analysis, was good for all compounds with the exception of compound 7i. In addition the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted in good candidates for BBB penetration.

Basic and clinical studies of prodrugs of nonsteroidal anti-inflammatory drugs.

Basic and clinical studies of prodrugs of nonsteroidal anti-inflammatory drugs.