吲哚胺2,3-双加氧酶2 (IDO2)在炎症特别是类风湿性关节炎(RA)方面的作用逐渐被阐明, IDO2成为RA治疗的潜在靶点. 目前尚未见活性强、选择性高的IDO2小分子抑制剂被报道. 以吲哚胺2,3-双加氧酶1 (IDO1)抑制剂epacadostat为先导化合物, 借助计算机辅助药物设计, 设计合成了24个未见文献报道的1,2,3-三氮唑类衍生物. 生物活性研究表明, 目标化合物均具有IDO1和IDO2酶抑制活性, 其中(Z)-N-((1-(2-((4-(N-(3-溴-4-氟苯基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)呋喃-2-甲酰胺(I-11)在100 nmol/L浓度下对IDO1和IDO2酶的抑制率分别为76%和49%, 优于先导化合物epacadostat(分别为62%和25%). 抗炎活性研究表明, 化合物I-11可有效抑制脂多糖(LPS)诱导的RAW264.7细胞炎症因子TNF-α的分泌, 并且对小鼠耳肿胀抑制率(56.81%, 100 mg/kg, 灌胃)优于阳性对照Naproxen (45.29%, 150 mg/kg, 灌胃), 表现出较好的抗炎活性.

As the role of indoleamine 2,3-dioxygenase 2 (IDO2) in inflammation, especially in rheumatoid arthritis (RA), is gradually being explained, IDO2 has become a potential target for the treatment of RA. No small molecule inhibitor of IDO2 with strong activity and high selectivity has been reported yet. With the help of computer-aided drug design, twenty-four 1,2,3-triazole derivatives were designed and synthesized by using epacadostat as a lead compound. The results of biological activity show that all target compounds display the inhibitory effects on IDO1 and IDO2 enzymes. Among them, the inhibition rates of (Z)-N-((1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyformamidine)-1,2,5-oxadiazo-3-yl)amino)ethyl)-1H-1,2,3- triazol-4-yl)methyl) (I-11) on indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 enzymes were 76% and 49% at 100 nmol/L concentration, respectively, which are better than those of epacadostat (62% and 25%). The anti-inflammatory activity study showed that compound I-11 could significantly inhibit the secretion of inflammatory factor TNF-α at the cellular level. Compound I-11 also showed good in vivo anti-inflammatory activity in mouse ear swelling model, and the inhibition rate was 56.81% at the dose of 100 mg/kg (Ig) which was better than that of naproxen (45.29%, 150 mg/kg, Ig).