This paper presents synthesis and structure–activity relationship of pyridine derivatives as inhibitors of mutant isocitrate dehydrogenase 2 (IDH2). A series of 2,4,6‐trisubstituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC₅₀ of 54.6 nm, which is approximately onefold improvement compared to drug candidate AG‐221 (Enasidenib) that is in Phase III trial. Exquisite selectivity of 14n for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the wild‐type IDH1 and IDH2.

中文翻译：

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发现一类新的选择性抑制突变异柠檬酸脱氢酶 2 的吡啶衍生物

本文介绍了作为突变异柠檬酸脱氢酶 2 (IDH2) 抑制剂的吡啶衍生物的合成和构效关系。已经制备了一系列 2,4,6-三取代吡啶衍生物并进行了体外评估。在这些化合物中，14n表现出优异的抑制活性，IC ₅₀为 54.6 nm，与处于 III 期试验的候选药物 AG-221 (Enasidenib) 相比提高了约一倍。14n对 IDH2 R140Q 突变异构体的高选择性表现在对野生型 IDH1 和 IDH2 的低活性。