Design, synthesis and in vitro evaluation of non-steroidal anti-inflammatory prodrugs for osteoarthritis

Osteoarthritis (OA), a degenerative joint disease characterized by chronic pain and stiffness, is the most common cause of disability in older adults. To date, OA lacks curative treatment and medical care is limited to symptom relief particularly through the use of oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, gastrointestinal and cardiovascular adverse effects and only limited benefits in long-term relief of pain are still associated. Moreover, efficiency is in part impeded by rapid clearance of the drugs and by the special physiological environment of the joint impeding deep penetration of drugs. Hence, to overcome those limitations and improve patient outcome, developing new therapeutic approaches based on anti-inflammatory prodrugs with prolonged drug residence time within the joints appears as a promising strategy in OA. We report herein the development of NSAID prodrugs, derived from diclofenac and naproxen, bearing a positively charged quaternary ammonium (QA) to target the negative-fixed charge density in cartilage by the mean of electrostatic interactions. Our charge-based targeted approach aims to extend the residence time of NSAID within the cartilaginous tissues, leading to a potential decrease of side effects and improved efficiency of locally released drugs. Syntheses of various amide and esters prodrugs of diclofenac and naproxen bearing a QA function were performed, including some hypoxia-activated prodrugs. Since most diclofenac derivatives suffered from high instability preventing any further development, we focused on the naproxen derivatives that were relatively stable in PBS buffer over a 24-h period even if three different degradation patterns were observed in murine plasma. A preliminary screening of their in vitro anti-inflammatory efficacy highlighted a correlation between the PGE-2 inhibition and these cleavage patterns. These results support further in vitro and in vivo evaluations of four of these derivatives in OA models.