sc-236 and rofecoxib

We have already demonstrated that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, has a proapoptotic effect on synovial fibroblasts obtained from patients with rheumatoid arthritis (RA). Here we report on the development of two novel derivatives of celecoxib, N-(2-aminoethyl)-4-[5-(4-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT101) and 4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT201), including whether these compounds have a proapoptotic effect on synovial fibroblasts. Synovial fibroblasts were harvested from the synovial tissues of patients with RA or osteoarthritis (OA). Cell proliferation and cell viability were assessed by the incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by the identification of DNA fragmentation, and activation of caspase-3 was detected by the addition of a caspase-3 substrate to cell lysates. Production of prostaglandin E(2) by RA synovial fibroblasts was analyzed by enzyme-linked immunosorbent assay. TT101 inhibited the proliferation of RA and OA synovial fibroblasts in a concentration-dependent manner. It caused a marked decrease of cell viability and induced DNA fragmentation more potently than either celecoxib or SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide). TT101 also increased caspase-3 activity. The order of potency of the COX-2 inhibitory activity of these drugs in RA synovial fibroblasts was celecoxib = SC-236 > rofecoxib > TT201 > TT101. In conclusion, we developed TT101 with about a 5- to 10-fold stronger proapoptotic effect on RA and OA synovial fibroblasts compared with that of celecoxib. Although the mechanism of action of TT101 remains unclear, it may have potential as a novel antirheumatic agent.

Topics: Apoptosis; Blotting, Western; Caspase Inhibitors; Caspases; Celecoxib; Cell Proliferation; Cell Survival; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprostone; DNA Fragmentation; Enzyme Inhibitors; Fibroblasts; Genes, bcl-2; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Synovial Membrane

To investigate whether and how treatment with COX-2 inhibitors influences hyaluronan responses to a standardized trauma, argon laser induced iritis, in rabbits.. Two different COX-2 inhibitors were used, SC-236 and rofecoxib. The drugs were administered orally, 6 mg/kg/day and 1.5 mg/kg/day respectively. Iris and aqueous humor hyaluronan concentrations were measured with a radiometric assay at different time points after laser irradiation.. The hyaluronan concentration in the iris increased 3-4-fold with a peak concentration of 129.1 microg/g wet weight 2 days after laser irradiation. It then decreased to normal values after 1 week. In eyes treated with either of the COX-2 inhibitors, iris hyaluronan concentrations did not decrease as rapidly and were significantly higher at day 4 and 7 when compared to drug untreated eyes.. Treatment with COX-2 inhibitors prolongs trauma induced elevation of iris content of endogenous hyaluronan. This may be, at least partly, due to an inhibition of interstitial fluid pressure regulation.

Topics: Animals; Aqueous Humor; Cyclooxygenase Inhibitors; Hyaluronic Acid; Iris; Iritis; Lactones; Low-Level Light Therapy; Pyrazoles; Rabbits; Sulfonamides; Sulfones

1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non-inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4. In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

Topics: Animals; Carrageenan; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Hindlimb; Hyperalgesia; Indomethacin; Inflammation; Isoenzymes; Lactones; Male; Pain Threshold; Piroxicam; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Sulfonamides; Sulfones