sc-236 and Osteoarthritis

To examine cyclooxygenase-2 (COX-2) enzyme expression, its regulation by interleukin-1 beta (IL-1 beta), and the role of prostaglandin E(2) (PGE(2)) in proteoglycan degradation in human osteoarthritic (OA) cartilage.. Samples of human OA articular cartilage, meniscus, synovial membrane, and osteophytic fibrocartilage were obtained at knee arthroplasty and cultured ex vivo with or without IL-1 beta and COX inhibitors. COX expression was evaluated by immunohistochemistry and Western blot analysis. The enzymatic activity of COX was measured by conversion of arachidonic acid to PGE(2). Cartilage degradation was evaluated by measuring the accumulation of sulfated glycosaminoglycans in the medium.. IL-1 beta induced robust expression of COX-2 and PGE(2) in OA meniscus, synovial membrane, and osteophytic fibrocartilage explants, whereas low levels were produced in OA articular cartilage. IL-1 beta also induced cartilage proteoglycan degradation in OA synovial membrane-cartilage cocultures. Increased proteoglycan degradation corresponded to the induction of COX-2 protein expression in, and PGE(2) production from, the synovial membrane. Dexamethasone, neutralizing IL-1 beta antibody, or the selective COX-2 inhibitor, SC-236, attenuated both the IL-1 beta-induced PGE(2) production and cartilage proteoglycan degradation in these cocultures. The addition of PGE(2) reversed the inhibition of proteoglycan degradation caused by SC-236.. IL-1 beta-induced production of COX-2 protein and PGE(2) was low in OA articular cartilage compared with that in the other OA tissues examined. IL-1 beta-mediated degradation of cartilage proteoglycans in OA synovial membrane-cartilage cocultures was blocked by the selective COX-2 inhibitor, SC-236, and the effect of SC-236 was reversed by the addition of exogenous PGE(2). Our data suggest that induction of synovial COX-2-produced PGE(2) is one mechanism by which IL-1 beta modulates cartilage proteoglycan degradation in OA.

Topics: Aged; Antibodies; Cartilage; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprostone; Female; Humans; Immunohistochemistry; In Vitro Techniques; Interleukin-1; Isoenzymes; Male; Membrane Proteins; Menisci, Tibial; Osteoarthritis; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Pyrazoles; Sulfonamides; Synovial Membrane

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Carrageenan; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Hyperalgesia; Isoenzymes; Magnetic Resonance Spectroscopy; Male; Membrane Proteins; Molecular Structure; Osteoarthritis; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides