Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2

Eur J Med Chem. 2021 Mar 26;218:113394. doi: 10.1016/j.ejmech.2021.113394. Online ahead of print.ABSTRACTHerein, 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.PMID:33813153 | DOI:10.1016/j.ejmech.2021.113394

Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Pengfei Xu Pei Shen Hai Wang Lian Qin Jie Ren Qiushuang Sun Raoling Ge Jinlei Bian Yi Zhong Zhiyu Li JuBo Wang Zhixia Qiu Source Type: research