Penning T D, Talley J J, Bertenshaw S R, Carter J S, Collins P W, Docter S, Graneto M J, Lee L F, Malecha J W, Miyashiro J M, Rogers R S, Rogier D J, Yu S S, Burton E G, Cogburn J N, Gregory S A, Koboldt C M, Perkins W E, Seibert K, Veenhuizen A W, Zhang Y Y, Isakson P C
Department of Chemistry, Searle Research and Development, Skokie, Illinois 60077, USA.
J Med Chem. 1997 Apr 25;40(9):1347-65. doi: 10.1021/jm960803q.
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.
制备了一系列含磺酰胺的1,5 - 二芳基吡唑衍生物，并对其在体外和体内阻断环氧合酶 - 2（COX - 2）的能力进行了评估。在该系列化合物中开展了广泛的构效关系（SAR）研究，确定了多种有效的COX - 2选择性抑制剂。由于早期的结构先导物（1f，SC - 236）表现出过长的血浆半衰期，令人难以接受，因此对一些含有潜在代谢位点的吡唑类似物进行了进一步的体内评估，以确定具有可接受药代动力学特征的化合物。这项工作促成了1i（4 - [5 - (4 - 甲基苯基)-3 - (三氟甲基)-H - 吡唑 - 1 - 基]苯磺酰胺，SC - 58635，塞来昔布）的发现，该化合物目前正处于治疗类风湿性关节炎和骨关节炎的III期临床试验阶段。
