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(+)] were synthesized. Compounds were labeled with tritium for piroxicam-N(+) and carbon-14 for propoxicam-N(+). Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages but their bioavailability by the oral way was low. Only propoxicam-N(+) exhibited a sufficient water solubility to be administered intravenously. This molecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1beta with an efficiency identical to 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 pharmacological activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and consequently an attenuation of adverse effects such as digestive toxicity.
Nicolas
C
C
INSERM Unité 484, Rue Montalembert, BP 184, 63005 Clermont-Ferrand Cedex, France.
Verny
M
M
Giraud
I
I
Ollier
M
M
Rapp
M
M
Maurizis
J C
JC
Madelmont
J C
JC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011509:Proteoglycans / Q000096:biosynthesis; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013843:Thiazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011509:Proteoglycans; D000644:Quaternary Ammonium Compounds; D013843:Thiazines