Tsuji K, Konishi N, Spears G W, Ogino T, Nakamura K, Tojo T, Ochi T, Shimojo F, Senoh H, Matsuo M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1997 Sep;45(9):1475-81. doi: 10.1248/cpb.45.1475.
A series of novel 1,5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30 = 0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50 = 21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.
制备了一系列带有亲水性取代基的新型1,5-二苯基吡唑衍生物。通过佐剂性关节炎和Randall-Selitto试验在大鼠中评估了这些化合物的抗炎和镇痛活性，并研究了构效关系。最佳化合物是3-(二氟甲基)-1-(4-甲氧基苯基)-5-[4-(甲基亚磺酰基)苯基]吡唑(10)，在佐剂性关节炎和角叉菜胶诱导的足水肿实验中，其口服ED50值分别为0.31和2.6 mg/kg。在Randall-Selitto试验中，化合物10不仅对发炎的爪子有镇痛活性，对正常爪子也有镇痛活性(ED30分别为0.55和1.8 mg/kg)，此外，10在夹尾试验中(ED50 = 21 mg/kg)与吗啡同样有效。还报道了10的对映体的不对称合成和药理性质。
