DRF-4367

For pharmacokinetic and toxicokinetic purpose a simple HPLC‐UV method has been developed and validated for the estimation of DRF‐4848, a novel COX‐2 inhibitor in rat plasma. A liquid–liquid extraction was used to extract DRF‐4848 and internal standard (IS, DRF‐4367) from rat plasma. The analysis was performed on a C18 column with UV detection at 285 nm. The isocratic mobile phase, 0.01 m potassium dihydrogen ortho phosphate (pH 3.2) and acetonitrile (50:50, v/v) was run at a flow rate of 1 mL/min. The retention times of DRF‐4848 and IS were 6.8 and 11.2 min, respectively. Absolute recovery for analyte and IS was >80% from rat plasma. A linear response was observed over a concentration range 0.1–20 mg/mL. The lower limit of quantification (LLOQ) of DRF‐4848 was 0.1 mg/mL. The inter‐ and intra‐day precisions in the measurement of quality control (QC) samples, 0.1, 0.3, 8.0 and 15.0 mg/mL, were in the range 1.74–8.70% relative standard deviation (RSD) and 0.75–8.43% RSD, respectively. Accuracy in the measurement of QC samples was in the range 93.29–116.51% of the nominal values. Analyte and IS were stable in the battery of stability studies viz., benchtop, autosampler, long‐term and freeze/thaw cycles. Copyright © 2006 John Wiley & Sons, Ltd.

Synthesis of prodrugs of orally active COX-2 inhibitor 3 involving sulfamoyl (SO(2)NH(2)) and hydroxymethyl (CH(2)OH) groups, and their biological evaluation are described. Of these prodrugs, the N-propionyl sulfonamide sodium 3k was found to be much superior to the parent compound 3 and other marketed COX-2 inhibitors in carrageenan induced rat paw edema model of inflammation due to highly elevated drug levels in systemic circulation. This prodrug has a potential both for oral as well as parenteral administration due to impressive analgesic activity, antipyretic potency, and extraordinary water solubility.