parecoxib-sodium and Edema

The synthesis and pharmacological evaluation of new water-soluble phosphoramidate derivatives of the COX-2 selective inhibitor cimicoxib (4) are described. The sulfonylphosphoramidic acid derivative 10 was converted to 4 in human plasma and showed excellent in vivo activity in the rat carrageenan-edema test. Pharmacokinetic evaluation in dogs indicated that 10 behaved as a prodrug, immediately converting to 4 and giving an identical profile to that of the parent compound. These results represent the first description of phosphoramidic acids as prodrugs for the sulfonamido group. Compound 10 also exhibited an important and sustained analgesic effect in the hyperalgesia test in rats and a high aqueous solubility at pH higher than 7. This profile led to the selection of 10 (UR-14048) for further development in the parenteral treatment of acute pain.

Topics: Acute Disease; Amides; Animals; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dogs; Edema; Half-Life; Humans; Hyperalgesia; Imidazoles; Isoenzymes; Male; Membrane Proteins; Pain Measurement; Phosphoric Acids; Prodrugs; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Solubility; Structure-Activity Relationship; Sulfonamides; Water

A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzenesulfonamides; Binding Sites; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Edema; Humans; Inhibitory Concentration 50; Isoenzymes; Male; Membrane Proteins; Models, Molecular; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sheep; Sodium; Spodoptera; Structure-Activity Relationship; Sulfonamides