Ester and Amide Prodrugs of Ibuprofen and Naproxen: Synthesis, Anti-inflammatory Activity, and Gastrointestinal Toxicity

Shanbhag, Vrinda R.; Crider, A. Michael; Gokhale, Rajeev; Harpalani, Anju; Dick, Ronald M.

doi:10.1002/jps.2600810210

Cited by 159 publications

(83 citation statements)

References 25 publications

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“…Ethanolamine and its related structures were chosen as modifications to dexibuprofen in the preparation of prodrugs. Although some ethanolamine derivatives of NSAIDs were synthesized to improve the anti-inflammatory activity of parent compounds and decrease gastrointestinal toxicity [25,26] , an investigation of their potential as brain targeting agents has not yet been performed. Ethanolamine is a commonly found small molecule.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

et al. 2012

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Aim: Dexibuprofen, the S(+)-isomer of ibuprofen, is an effective therapeutic agent for the treatment of neurodegenerative disorders. However, its clinical use is hampered by a limited brain distribution. The aim of this study was to design and synthesize brain-targeting dexibuprofen prodrugs and to evaluate their brain-targeting efficiency using biodistribution and pharmacokinetic analysis. Methods: In vitro stability, biodistribution and pharmacokinetic studies were performed on male Sprague-Dawley rats. The concentrations of dexibuprofen in biosamples, including the plasma, brain, heart, liver, spleen, lung, and kidney, were measured using high pressure lipid chromatography (HPLC). The pharmacokinetic parameters of the drug in the plasma and tissues were calculated using obtained data and statistics. Results: Five dexibuprofen prodrugs that were modified to contain ethanolamine-related structures were designed and synthesized. Their chemical structures were confirmed using 1 H NMR, 13 C NMR, IR, and HRMS. In the biodistribution study, 10 min after intravenous administration of dexibuprofen (11.70 mg/kg) and its prodrugs (the dose of each compound was equivalent to 11.70 mg/kg of dexibuprofen) in male Sprague-Dawley rats, the dexibuprofen concentrations in the brain and plasma were measured. The C brain /C plasma ratios of prodrugs 1, 2, 3, 4, and 5 were 17.0-, 15.7-, 7.88-, 9.31-, and 3.42-fold higher than that of dexibuprofen, respectively (P<0.01). Thus, each of the prodrugs exhibited a significantly enhanced brain distribution when compared with dexibuprofen. In the pharmacokinetic study, prodrug 1 exhibited a brain-targeting index of 11.19 {DTI=(AUC brain /AUC plasma ) 1 /(AUC brain /AUC plasma ) dexibuprofen }. Conclusion:The ethanolamine-related structures may play an important role in transport across the brain blood barrier.

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Section: Introductionmentioning

confidence: 99%

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

et al. 2012

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“…However, it always brings about serious gastrointestinal side effects such as ulcers, bleeding, and gastric perforation in long-term administration [1]. Carboxylic acid group on the propionic acid molecules is the main reason causing gastrointestinal adverse reaction [2]. In order to reduce side effects of naproxen, we have synthesized a Naproxen-Paeonol ester as a prodrug.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 2-acetyl-5-methoxyphenyl 2-(6-methoxynaphthalen-2-yl) propanoate, C23H22O5

Dong

Yang

et al. 2013

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of material Naproxen (0.015 mol, 3.45 g) was dissolved in anhydrous methylene chloride (12 mL), and then oxalyl chloride (0.018 mol, 1.7 mL) and two drops of N, N-dimethylformamide was dropwise added at 0°C. The solution was stirred overnight at room temperature. After the solvent and excess oxalyl chloride was removed by vacuum distillation, the residue was washed three times with dry toluene to obtain a yellow solid, naproxen acylchloride. Paeonol, 1-(2-hydroxy-4-methoxyphenyl)-ethanone (0.01 mol, 1.66 g) and 4-(dimethylamino)-pyridin (DMAP, 0.0015 mol, 0.18 g) were dissolved in dry tetrahydrofuran (20 mL) and triethylamine (0.015 mol, 2 mL). To the solution a solution of naproxen acylchloride in dry tetrahydrofuran was dropwise added at 0°C. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was filtrated to remove the solid and the filtrate was concentrated under vacuum to remove the solvent. The residue was dissolved in methylene chloride, successively washed with 5% NaHCO 3 solution and water to pH = 7, and dried with anhydrous Na 2 SO 4 . The solution was filtrated, and concentrated under vacuum to obtain crude product. The crude product was purified by recrystallization in ethyl acetate. The single crystals were obtained from methanol solution. Experimental detailsAll the carbon-bounded H atoms were positioned geometrically with d(C-H) = 0.93-0.98 Å and U iso (H) = 1.2 or 1.5 U eq (C).

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“…Ibuprofen (2-(4-isobutylphenyl)propionic acid) is an important non-steroidal anti-inflammatory drug that is widely used for the treatment of headaches, rheumatoid arthritis, and muscular strains [1][2][3]. Commercially available ibuprofen is usually a racemic mixture, as the racemate is easily obtained through chemical synthesis.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Hydrolytic Resolution of Racemic Ibuprofen Ethyl Ester Using an Ionic Liquid as Cosolvent

et al. 2016

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Abstract:The aim of this study was to develop an ionic liquid (IL) system for the enzymatic resolution of racemic ibuprofen ethyl ester to produce (S)-ibuprofen. Nineteen ILs were selected for use in buffer systems to investigate the effects of ILs as cosolvents for the production of (S)-ibuprofen using thermostable esterase (EST10) from Thermotoga maritima. Analysis of the catalytic efficiency and conformation of EST10 showed that [OmPy] [BF 4 ] was the best medium for the EST10-catalyzed production of (S)-ibuprofen. The maximum degree of conversion degree (47.4%), enantiomeric excess of (S)-ibuprofen (96.6%) and enantiomeric ratio of EST10 (177.0) were achieved with an EST10 concentration of 15 mg/mL, racemic ibuprofen ethyl ester concentration of 150 mM, at 75˝C , with a reaction time of 10 h. The reaction time needed to achieve the highest yield of (S)-ibuprofen was decreased from 24 h to 10 h. These results are relevant to the proposed application of ILs as solvents for the EST10-catalyzed production of (S)-ibuprofen.

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Ester and Amide Prodrugs of Ibuprofen and Naproxen: Synthesis, Anti-inflammatory Activity, and Gastrointestinal Toxicity

Cited by 159 publications

References 25 publications

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

Crystal structure of 2-acetyl-5-methoxyphenyl 2-(6-methoxynaphthalen-2-yl) propanoate, C23H22O5

Enzymatic Hydrolytic Resolution of Racemic Ibuprofen Ethyl Ester Using an Ionic Liquid as Cosolvent

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