Design, Synthesis and antiinflammatory activity of novel gamma-tocopherol naproxen ester prodrug

Naproxen is widely used for the treatment of arthritic pain. It can induce gastrointestinal (GI) side effects ranging from stomach irritation to ulceration and bleeding. These complications are believed to be determined from the combined effect of the blockage of prostaglandin biosynthesis in the GI tract and direct action of free carboxylic groups. Prodrugs approach have been proposed to overcome the Non-steroidal anti-inflammatory drugs (NSAIDs) side effects by masking the carboxylic acid groups via formation of bioreversible bonds. It has been demonstrated that the production of reactive oxygen species (ROS) plays an important pathogenic role in gastrointestinal ulceration. Our goal was to develop a new Naproxen prodrug which integrates the concepts of prodrug and the beneficial antioxidant effect. For this purpose we designed and synthesized naproxen esters containing tocopherols. Among the possible antioxidant compounds we focused our attention on γ-tocopherol for its potent antioxidant properties and anti-inflammatory activity. In addition, esterification of phenolic group on chroman ring of tocopherols, to form the prodrug, is expected to increase the stability to oxidation of the vitamin. In the present paper, we report the synthesis and the in vitro enzymatic and non-enzymatic hydrolysis of two prodrug esters of naproxen with α- and γ-tocopherols. We also investigated the oral pharmacokinetic in rabbit and probed the preliminary pharmacological evaluation in rat. The synthesized prodrugs exhibited anti-inflammatory activity with a strong and significant reduction in gastrolesivity