Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1 H -pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)

作者：Thomas D. Penning, John J. Talley, Stephen R. Bertenshaw, Jeffery S. Carter, Paul W. Collins, Stephen Docter, Matthew J. Graneto, Len F. Lee, James W. Malecha, Julie M. Miyashiro, Roland S. Rogers, D. Joseph Rogier, Stella S. Yu, Gary D. Anderson, Earl G. Burton, J. Nita Cogburn, Susan A. Gregory, Carol M. Koboldt, William E. Perkins, Karen Seibert, Amy W. Veenhuizen, Yan Y. Zhang, Peter C. Isakson · 发表于：Journal of Medicinal Chemistry · 年份：1997 · DOI：10.1021/jm960803q · 被引用次数：1967 · 研究领域：Inflammatory mediators and NSAID effects、Synthesis and biological activity、Synthesis and Reactivity of Sulfur-Containing Compounds

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.