Baba A, Kawamura N, Makino H, Ohta Y, Taketomi S, Sohda T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
J Med Chem. 1996 Dec 20;39(26):5176-82. doi: 10.1021/jm9509408.
In the course of our study aimed at developing new types of DMARDs (disease-modifying antirheumatic drugs), we found that quinoline derivative 1a had a potent anti-inflammatory effect in an adjuvant arthritis (AA) rat model, starting from the potent bone resorption inhibitors justicidins as the lead compounds. Further modification of 1a was performed, and various quinoline and quinazoline derivatives having a heteroaryl moiety on the alkyl side chain at the 2-position of the skeleton were prepared. These compounds were evaluated for anti-inflammatory effects using the AA rat model. Most of these compounds, especially those having an imidazole or a triazole moiety on the 2-alkyl chain, exhibited a potent effect. Among the compounds synthesized, ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (12d), having an ED50 value of 2.6 mg/kg/day (anti-inflammatory effect in an AA rat model, po), was selected as a candidate for further investigation. In vitro, 12d inhibited mitogen-induced proliferation at 10(-7)-10(-5) M but not prostaglandin E2 production at 10(-5) M. Moreover, 12d preferentially inhibited the IFN-gamma production by Th1-type clones over the IL-4 production by Th2-type clones. This preferential suppression of Th1 cytokine production is considered the essential immunomodulating action of 12d for the present. Synthesis and structure-activity relationships for this novel series of quinoline and quinazoline derivatives are detailed.
在我们旨在开发新型改善病情抗风湿药（DMARDs）的研究过程中，我们发现喹啉衍生物1a在佐剂性关节炎（AA）大鼠模型中具有强大的抗炎作用，该研究始于以强效骨吸收抑制剂正义霉素为先导化合物。对1a进行了进一步修饰，制备了各种在骨架2位的烷基侧链上具有杂芳基部分的喹啉和喹唑啉衍生物。使用AA大鼠模型对这些化合物的抗炎作用进行了评估。这些化合物中的大多数，尤其是那些在2-烷基链上具有咪唑或三唑部分的化合物，表现出强大的作用。在合成的化合物中，4-(3,4-二甲氧基苯基)-6,7-二甲氧基-2-(1,2,4-三唑-1-基甲基)喹啉-3-羧酸乙酯（12d），口服给药时在AA大鼠模型中的ED50值为2.6 mg/kg/天（抗炎作用），被选为进一步研究的候选药物。在体外，12d在10(-7)-10(-5) M浓度下抑制有丝分裂原诱导的增殖，但在10(-5) M浓度下不抑制前列腺素E2的产生。此外，12d优先抑制Th1型克隆产生的IFN-γ，而不是Th2型克隆产生的IL-4。目前认为这种对Th1细胞因子产生的优先抑制是12d的基本免疫调节作用。详细阐述了这一系列新型喹啉和喹唑啉衍生物的合成及构效关系。
