Design, synthesis and hydrolytic behavior of mutual prodrugs of NSAIDs with gabapentin using glycol spacers.

Monther Mahdi,Hiba Alsaad

doi:10.3390/ph5101080

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.

Highlights

Non steroid anti-inflammatory drugs (NSAIDs) such as mefenamic acid (1), naproxen (2) and ibuprofen (3) that are represented in Figure 1 constitute a group of heterogeneous molecules that account for a large share of the drug market [1]
The relationship between oral intake of NSAIDs and gastrointestinal (GI) side effects like gastric irritation, ulceration, bleeding, and in some cases life threatening conditions, restrict their clinical usefulness [7], so this is the impetus for the development of effective NSAIDs with more favorable GI safety profiles
The white precipitate of dicyclohexyl urea (DCU) that formed was separated by filtration and the filtrate was concentrated by evaporation, the precipitate redissolved in ethyl acetate (20 mL) and washed with HCI (0.05 N, 20 mL), 5% sodium bicarbonate and water, respectively, and dried over anhydrous NaSO4 [25], the solvent was evaporated and the products were recrystallized from n-hexane; ethyl acetate-n-hexane and methanol to give compounds 8a–d respectively

Summary

Introduction

Non steroid anti-inflammatory drugs (NSAIDs) such as mefenamic acid (1), naproxen (2) and ibuprofen (3) that are represented in Figure 1 constitute a group of heterogeneous molecules that account for a large share of the drug market [1] These compounds possess one or more anti-inflammatory properties such as analgesic, anti-pyretic, and edema-reducing effect, so they are used for the long and short term management of various conditions, include osteoarthritis, rheumatoid arthritis [2], and musculoskeletal pain [3]. Different types of pain have been identified such as inflammatory pain, that refers to the pain occurring in response to tissue injury and accompanied by a neurogenic inflammation It results from the release of sensitizing inflammatory substances. Another type of pain is neuropathic pain which is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [11,12]

Methods

Results

Conclusion