Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors

作者全名："Tian, Yang; Qin, Songhui; Zhang, Fang; Luo, Jing; He, Xi; Sun, Yi; Yang, Tao"

作者地址："[Tian, Yang; Zhang, Fang; Luo, Jing; He, Xi; Sun, Yi] Chongqing Med Univ, Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Hosp Affiliated 2,Affiliated Hosp,Dept Oto, Chengdu 610014, Peoples R China; [Tian, Yang] Chongqing Med Univ, Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Affiliated Hosp,Chengdu Hosp Affiliated 2,Med Res, Chengdu 610014, Peoples R China; [Qin, Songhui; Yang, Tao] Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Chengdu 610041, Peoples R China; [Qin, Songhui; Yang, Tao] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China"

通信作者："Yang, T (通讯作者)，Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Chengdu 610041, Peoples R China.; Yang, T (通讯作者)，Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China."

来源：ACS MEDICINAL CHEMISTRY LETTERS

ESI学科分类：CHEMISTRY

WOS号：WOS:001039191100001

JCR分区：Q2

影响因子：3.5

年份：2023

卷号：14

期号：8

开始页：1113

结束页：1121

文献类型：Article

关键词：JAK2; Selectivity; Inhibitors; Myeloproliferativeneoplasms; Pharmacokinetics

摘要："The JAK2(V617F) mutation leads to JAK2 autophosphorylationand activation of downstream pathways, eventually resulting in myelo-proliferativeneoplasms (MPNs). Selective inhibitors showed advantages in termsof side effects; therefore, there is an urgent need to develop novelselective JAK2 inhibitors for treating MPNs. In this study, we describeda series of N-(4-(aminomethyl)-phenyl)-pyrimidin-2-aminederivatives as selective JAK2 inhibitors. Systematic exploration throughopening the tetrahydro-isoquinoline based on the previous leadcompound 13ac led to the discovery of the optimal compound A8. Compound A8 showed excellent potency on JAK2kinase, with an IC50 value of 5 nM, and inhibited the phosphorylationof JAK2 and its downstream signaling pathway. Moreover, A8 exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3,and TYK2, respectively. Compared to the lead compound, A8 demonstrated much better metabolic stabilities, with a bioavailabilityof 41.1%. These findings suggest that A8 is a relativelyselective JAK2 inhibitor, deserving to be developed for treating MPNs."

基金机构：National Natural Science Foundation of China [82204191]; Natural Science Foundation of Sichuan Province [2022NSFSC1341]; China Postdoctoral Science Foundation [2022M712279]

基金资助正文："The authors greatly appreciate the financial support from the National Natural Science Foundation of China (82204191), the Natural Science Foundation of Sichuan Province (no. 2022NSFSC1341), and the China Postdoctoral Science Foundation (no. 2022M712279)."