| Autor: |
Song, Y., Connor, D. T., Sercel, A. D., Sorenson, R. J., Doubleday, R., Unangst, P. C., Roth, B. D., Beylin, V. G., Gilbertsen, R. B., Chan, K., Schrier, D. J., Guglietta, A., Bornemeier, D. A., Dyer, R. D. |
| Zdroj: |
Journal of Medicinal Chemistry; April 8, 1999, Vol. 42 Issue: 7 p1161-1169, 9p |
| Abstrakt: |
Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 μM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 μM and inhibited COX-1 activity in platelets with an IC50 of 3.1 μM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7.1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes. |
| Databáze: |
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