Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)
Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)
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DOI：
10.1021/jm960803q
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发表时间：
1997-04-25
影响因子：
7.3
通讯作者：
Isakson, PC
中科院分区：
文献类型：
--
作者：
Penning, TD;Talley, JJ;Isakson, PC
合成了一系列含磺酰胺基的1，5-二芳基吡唑衍生物，并评价了它们在体内外对环氧合酶-2（考克斯-2）的阻断作用。广泛的结构-活性关系（SAR）的工作进行了这一系列，并确定了一些有效的和选择性的考克斯-2抑制剂。由于早期结构先导化合物（1f，SC-236）的血浆半衰期长得不可接受，因此进一步在体内评价了许多含有潜在代谢位点的吡唑类似物，以确定具有可接受药代动力学特征的化合物。这项工作导致了ii（4-[5-（4-甲基苯基）-3-（三氟甲基）-1H-吡唑-1-基]苯磺酰胺，SC-58635，塞来昔布）的鉴定，其目前处于治疗类风湿性关节炎和骨关节炎的III期临床试验中。
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 ii (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.