Tsuji K, Nakamura K, Konishi N, Tojo T, Ochi T, Senoh H, Matsuo M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka Japan.
Chem Pharm Bull (Tokyo). 1997 Jun;45(6):987-95. doi: 10.1248/cpb.45.987.
A series of novel 1,5-diarylpyrazole derivatives was synthesized and tested for anti-inflammatory and analgesic activities to develop anti-inflammatory agents with fewer side effects than existing nonsteroidal anti-inflammatory drugs. The structure-activity relationships in this series were extensively studied. Electron-withdrawing substituents such as CN and CF3 were optimal at the 3-position of the pyrazole ring. Replacement of these substituents with bulky ones gave less active compounds. The 4-(methylsulfonyl)phenyl group seemed to be the optimal group at the 5-position of the pyrazole ring. The most potent compound was 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyrazole-3-carbonitrile (19a), with oral ED50 value of 0.030 and 0.47 mg/kg on adjuvant-induced arthritis and collagen-induced arthritis, respectively, and an ED30 value of 7.4 mg/kg in the yeast-induced hyperalgesia (Randall-Selitto) assay. Compound 19a also showed potent inducible cyclooxygenase (COX-2)-inhibitory activity (IC50 = 0.24 microM) with no COX-1 inhibition even at 100 microM.
合成了一系列新型1,5 - 二芳基吡唑衍生物，并对其抗炎和镇痛活性进行了测试，以开发出比现有非甾体抗炎药副作用更少的抗炎药。对该系列化合物的构效关系进行了广泛研究。吸电子取代基如CN和CF3在吡唑环的3 - 位是最佳的。用体积较大的取代基取代这些取代基会得到活性较低的化合物。4 - （甲基磺酰基）苯基似乎是吡唑环5 - 位的最佳基团。最有效的化合物是1 - （4 - 氟苯基）-5 - [4 - （甲基磺酰基）苯基] - 吡唑 - 3 - 腈（19a），在佐剂性关节炎和胶原诱导性关节炎模型中，口服ED50值分别为0.030和0.47 mg/kg，在酵母诱导的痛觉过敏（Randall - Selitto）试验中的ED30值为7.4 mg/kg。化合物19a还显示出强效的诱导型环氧化酶（COX - 2）抑制活性（IC50 = 0.24 microM），即使在100 microM时也没有COX - 1抑制作用。
