New quaternary ammonium oxicam derivatives targeted toward cartilage: Synthesis, pharmacokinetic studies, and antiinflammatory potency

Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the active group was linked to a quaternary ammonium function [(4-hydroxy- 2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxamido)2-methylpyridinium iodide or piroxicam-N+ and [3-(4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1- dioxide-3-carboxamido)propyl]trimethylammonium iodide or propoxicam-N+] wer e synthesized. Compounds were labeled with tritium for piroxicam-N+ and car bon-14 for propoxicam-N+. Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages bu t their bioavailability by the oral way was low. Only propoxicam-N+ exhibit ed a sufficient water solubility to be administered intravenously. This mol ecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1 beta with an efficiency identical t o that of indomethacin. These results suggest that the functionalization of oxicam derivatives by a quaternary ammonium group greatly increases their affinity toward articular cartilage without eliminating their pharmacologic al activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and co nsequently an attenuation of adverse effects such as digestive toxicity.