Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2.

Pengfei Xu, Pei Shen, Hai Wang, Lian Qin, Jie Ren, Qiushuang Sun, Raoling Ge, Jinlei Bian, Yi Zhong, Zhiyu Li, JuBo Wang, Zhixia Qiu

European journal of medicinal chemistry 2021 Jun 05

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Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Citation

Pengfei Xu, Pei Shen, Hai Wang, Lian Qin, Jie Ren, Qiushuang Sun, Raoling Ge, Jinlei Bian, Yi Zhong, Zhiyu Li, JuBo Wang, Zhixia Qiu. Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2. European journal of medicinal chemistry. 2021 Jun 05;218:113394