Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
Changzhou Siyao Pharmaceutical Co. Ltd. No.567, Zhongwu Avenue, Changzhou, Jiangsu, 213018, China.
Eur J Med Chem. 2021 Jun 5;218:113394. doi: 10.1016/j.ejmech.2021.113394. Epub 2021 Mar 26.
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 IC 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 (T = 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.
本文描述了一系列选择性抑制 Janus 激酶 2（JAK2）的咪唑并吡咯吡啶衍生物的设计、合成和构效关系。这些筛选级联反应表明，6k 是一种优选的化合物，对 JAK2 的 IC 值为 10 nM。此外，6k 是一种选择性 JAK2 抑制剂，对 JAK1、JAK3 和 TYK2 的选择性分别为 19 倍、>30 倍和>30 倍。在细胞因子刺激的基于细胞的测定中，6k 在 JAK2 选择性方面优于 JAK1 同工型。实际上，在 20 mg/kg 化合物 6k 的剂量下，pSTAT3 和 pSTAT5 的表达水平降低到与未用 GM-CSF 处理的对照动物相当的水平。此外，6k 表现出相对良好的生物利用度（F = 38%）、合适的半衰期（T = 1.9 h）和令人满意的代谢稳定性，这表明 6k 可能是一种有前途的 JAK2 抑制剂，可进一步开发用于治疗 MPNs。
