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.
Rue Montalembert -63005 Clennont-Fermnd Ceder INSERM U 71 -E.P. 184 -SUMMARY m e easy prepamtion of 2-bromo E I -~H I ethanol allows the tritium labelling of molecules bearing S-or Nhydroxyethyl groups. Thus S-0-hydroxy [2-HI ethyl) glutathione and [3HfMelphalan were qmthesised with specific mdioactivities of around 10 mCi/mmol (370 MBq/mmol). These values could be theoretically mised to 10 .Ci/mmol (370 GBq/mmol), according to the specific activity of the labelling precursor, sodium ?HI borohydride.
K~u o r d s :
2-Hydraxy C2-3Hl ethyl groups
S-(2-hydmxy 12-3Hl ethyl) glutathione ?HI MelphahnINTRODUCnON 2-Chloroethanol was identified in plasma and after oxidation into 2-chloroacetaldehyde, appeared to be elfminoted mainly as four sulphur containing metabolites (1,2). Two intermediates in this metabolic scheme could be S-(2-chloroethyl) glutathione and S-(2-hydmxyethyl) glutathione (3), the latter being expected to exhibit high concentmtions in thymus and pancreas.In order to study the metabolism and Modisposttion of RFNCU and RPNCU, it WQS useful to synthesize the s u p p e d intermediates as labelled species. The S-alkylation of glutathione by the means of ethylene oxide (available as the [ CJlabelled reagent), according to the method described by Johnson (41, failed to @w the expected results. Thus, following the methods of Z i h and Weinstein (5) and Nachtomi (6), we attempted to use bornoathano1 as the alkylating reagent (Scheme 11, on the assumption that the ?HJlabelled compound could be easily obtained, by the reduction of ethyl bromwcetate WIth a trttiated hydride : Unit 71, led to the proposal of a biotmnsformation scheme in animals (I). 1 4 0362 -4803/88/090949 -07505.00 0 1988 by John Wiky & Sons, Ltd.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.