State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2019 May 1;169:121-143. doi: 10.1016/j.ejmech.2019.02.077. Epub 2019 Mar 6.
A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC = 3.0 nM against BTK enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.
一系列 7H-吡咯并[2,3-d]嘧啶衍生物被设计和合成作为可逆 BTK 抑制剂，并评估了它们在体外对 B 细胞淋巴瘤细胞系（Ramos、Jeko-1）和细胞系 BTK 增强（Daudi）的激酶选择性和抗增殖活性。其中，化合物 28a 表现出最优异的活性（对 BTK 酶的 IC50 为 3.0 nM，对 Ramos、Jeko-1、Daudi 细胞的抑制活性分别为 8.52 μM、11.10 μM 和 7.04 μM），良好的激酶选择性，并抑制 BTK Y223 自身磷酸化和 PLCγ2 Tyr1217 磷酸化。重要的是，28a 在体内胶原诱导性关节炎（CIA）模型中显示出有效的抗关节炎作用。28a 每天 60mg/kg 剂量组显示出明显减轻的关节损伤和细胞浸润，而没有任何骨和软骨形态变化。
