Combining Anticholinergic and Anti‐inflammatory Activities into a Single Moiety: A Novel Approach to Reduce Gastrointestinal Toxicity of Ibuprofen and Ketoprofen

Halen, Parmeshwari K.; Chagti, Kewal K.; Giridhar, Rajani; Yadav, Mange Ram

doi:10.1111/j.1747-0285.2007.00574.x

Cited by 17 publications

(18 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The resulting dexibuprofen chloride was coupled with the hydroxyl group of ethanolamine-related structures via an ester bond. To generate N,N-disubstituted ethanolamine, esterification was performed in a one-step reaction by mixing commercially available N,N-dimethylaminoethanol or N,N-diethylaminoethanol with dexibuprofen chloride in anhydrous dichloromethane (CH 2 Cl 2 ) in the presence of triethylamine (TEA) to give target prodrug 1 or 2 in high yield [26] . For aminoethanol or 2-(methylamino)ethanol, which has a free H atom at the amino group, the amino group was protected by ditertbutyldicarbonate in the first step.…”

Section: Chemistrymentioning

confidence: 99%

“…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%

See 1 more Smart Citation

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The anti-inflammatory activity was carried out according to the method of Halen et al 20 and employed with some modifications. 18 Sprague Dawley rats were used for this study; seventeen groups with six rats per group were formed.…”

Section: Anti-inflammatory Activitymentioning

confidence: 99%

“…19 Further, these compounds were subjected for their analgesic and antiinflammatory activity by the carrageenan induced rat paw edema model 20 and Eddy's hot plate method, 21 respectively. After evaluation for pharmacological studies, it becomes necessary to determine the safety of synthesized compounds with respect to ulcerogenesis study or the determination of severity index with respect to reference drug such as indomethacin.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

Kerzare¹,

Chikhale²,

Bansode³

et al. 2016

Journal of the Brazilian Chemical Society

View full text Add to dashboard Cite

The manuscript describes design and synthesis of novel oxadiazolyl-2-oxoindolinylidene propane hydrazides as amide tethered hybrids of indole and oxadiazole and their evaluation for antiinflammatory and analgesic activity. The compounds were synthesized following five step reaction to yield fifteen derivatives as 3- (5-propane hydrazide and 3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]propane hydrazide were found to be highly promising molecules with severity index of 0.35 and 0.56, respectively, which is promising for an analgesic compound. The hydroxy and methyl substitution on phenyl ring system provided with active anti-inflammatory compounds having increase in reaction time of 84.11 and 83.17%, respectively compared to standard drug at 85.84%. Molecular docking studies exhibit comparable interaction with synthesized derivatives and standard drug having a dock score of −4.44 by the K-nearest neighbour genetic algorithm method.

show abstract

“…Flurbiprofen chloride was first prepared by treating FLU (2.05 mmol, 500 mg) with SOCl 2 at reflux for 3 h followed by evaporation under reduced pressure, as reported before (Song et al, 2004). The oily residue was dissolved in 4 ml anhydrous dichloromethane and was added dropwise into 4 ml TEA alkalized dichloromethane containing N,N-dimethylethylenediamine (4.1 mmol, 446.7 ml) or N,N-dimethyl ethanolamine (4.1 mmol, 415.5 ml) in ice-water bath (Halen et al, 2007). The reaction mixture was then stirred at 35 C for 1 h. After that, the solvent was diluted and washed several times with brine to quench the reaction and remove some hydrophilic hybrids.…”

Section: Synthesis Of Flu Derivativesmentioning

confidence: 99%

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

Zheng

Xiao

et al. 2014

Drug Delivery

View full text Add to dashboard Cite

Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolaminerelated structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its C max and AUC 0-t were enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the braintargeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.

show abstract

Combining Anticholinergic and Anti‐inflammatory Activities into a Single Moiety: A Novel Approach to Reduce Gastrointestinal Toxicity of Ibuprofen and Ketoprofen

Cited by 17 publications

References 15 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

Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

Contact Info

Product

Resources

About