Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2013 Nov 28

PMID 24281258

Citations 2

Authors

Monther Faisal Mahdi

Hiba Najeh Alsaad

Affiliations

Soon will be listed here.

Abstract

The free –COOH present in NSAIDs is thought to be responsible for the GI irritation associated with all traditional NSAIDs. Exploitation of mutual prodrugs is an approach wherein the NSAID is covalently bounded to a second pharmacologically active carrier/drug with the ultimate aim of reducing the gastric irritation. In this study some NSAIDs were conjugated with gabapentin via ester bonds using glycol spacers with the expectation of reducing gastric adverse effects and obtaining synergistic analgesic effects. The kinetics of ester hydrolysis were studied in two different non enzymatic buffer solutions at pH 1.2 and 7.4, as well as in 80% human plasma using HPLC with chloroform -methanol as mobile phase. Compounds 9a–c with ethylene glycol spacers showed significant stability at buffer solutions with half lives ranging from about 8–25 h, while the underwent a reasonable plasma hydrolysis (49%–88%) in 2 h. Compound 9d with a propylene glycol spacer shows a higher rate of enzymatic hydrolysis than the corresponding ethylene glycol compound 9c. The result of compounds 9a-c indicate that these compounds may be stable during their passage through the GIT until reaching the blood circulation.

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References

Wittine K, Benci K, Rajic Z, Zorc B, Kralj M, Marjanovic M . The novel phosphoramidate derivatives of NSAID 3-hydroxypropylamides: synthesis, cytostatic and antiviral activity evaluations. Eur J Med Chem. 2008; 44(1):143-51. DOI: 10.1016/j.ejmech.2008.03.037. View

Khansari P, Halliwell R . Evidence for neuroprotection by the fenamate NSAID, mefenamic acid. Neurochem Int. 2009; 55(7):683-8. DOI: 10.1016/j.neuint.2009.06.014. View

Hamad M, Kiptoo P, Stinchcomb A, Crooks P . Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents. Bioorg Med Chem. 2006; 14(20):7051-61. DOI: 10.1016/j.bmc.2006.06.018. View

Lee B, Yoon C, Osipov A, Moghavem N, Nwachokor D, Amatya R . Nanoprodrugs of NSAIDs: Preparation and Characterization of Flufenamic Acid Nanoprodrugs. J Drug Deliv. 2011; 2011:980720. PMC: 3095474. DOI: 10.1155/2011/980720. View

Scheiman J, Hindley C . Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther. 2010; 32(4):667-77. DOI: 10.1016/j.clinthera.2010.04.009. View

Biyik I, Gulculer M, Karabiga M, Ergene O, Tayyar N . Efficacy of gabapentin versus diclofenac in the treatment of chest pain and paresthesia in patients with sternotomy. Anadolu Kardiyol Derg. 2009; 9(5):390-6. View

Tomisato W, Tsutsumi S, Hoshino T, Hwang H, Mio M, Tsuchiya T . Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions. Biochem Pharmacol. 2004; 67(3):575-85. DOI: 10.1016/j.bcp.2003.09.020. View

Sills G . The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2005; 6(1):108-13. DOI: 10.1016/j.coph.2005.11.003. View

Abdel-Azeem A, Abdel-Hafez A, El-Karamany G, Farag H . Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies. Bioorg Med Chem. 2009; 17(10):3665-70. DOI: 10.1016/j.bmc.2009.03.065. View

10.

Qandil A, Rezigue M, Tashtoush B . Synthesis, characterization and in vitro hydrolysis of a gemfibrozil-nicotinic acid codrug for improvement of lipid profile. Eur J Pharm Sci. 2011; 43(3):99-108. DOI: 10.1016/j.ejps.2011.03.012. View

11.

Kalgutkar A, Marnett A, Crews B, Remmel R, Marnett L . Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem. 2000; 43(15):2860-70. DOI: 10.1021/jm000004e. View

12.

Burian M, Geisslinger G . COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther. 2005; 107(2):139-54. DOI: 10.1016/j.pharmthera.2005.02.004. View

13.

Ajmone-Cat M, Bernardo A, Greco A, Minghetti L . Non-Steroidal Anti-Inflammatory Drugs and Brain Inflammation: Effects on Microglial Functions. Pharmaceuticals (Basel). 2016; 3(6):1949-1965. PMC: 4033961. DOI: 10.3390/ph3061949. View

14.

Mizushima T . Molecular Mechanism for Various Pharmacological Activities of NSAIDS. Pharmaceuticals (Basel). 2016; 3(5):1614-1636. PMC: 4034000. DOI: 10.3390/ph3051614. View

15.

Finnerup N, Sindrup S, Jensen T . The evidence for pharmacological treatment of neuropathic pain. Pain. 2010; 150(3):573-581. DOI: 10.1016/j.pain.2010.06.019. View

16.

Bennett M, Simpson K . Gabapentin in the treatment of neuropathic pain. Palliat Med. 2004; 18(1):5-11. DOI: 10.1191/0269216304pm845ra. View