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

doi:10.1016/j.ejmech.2021.113394

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2

Eur J Med Chem. 2021 Jun 5:218:113394. doi: 10.1016/j.ejmech.2021.113394. Epub 2021 Mar 26.

Authors

Pengfei Xu¹, Pei Shen¹, Hai Wang², Lian Qin¹, Jie Ren¹, Qiushuang Sun¹, Raoling Ge³, Jinlei Bian⁴, Yi Zhong⁴, Zhiyu Li⁵, JuBo Wang⁴, Zhixia Qiu⁴

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
² Changzhou Siyao Pharmaceutical Co. Ltd. No.567, Zhongwu Avenue, Changzhou, Jiangsu, 213018, China.
³ Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, 650000, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China. Electronic address: zhiyuli@cpu.edu.cn.

PMID: 33813153
DOI: 10.1016/j.ejmech.2021.113394

Abstract

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 (T_1/2 = 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.

Keywords: Imidazopyrrolopyridine; Janus kinase 2 (JAK2); Kinase; Myeloproliferative neoplasms; Selectivity.

MeSH terms

Cells, Cultured
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

Imidazoles
Protein Kinase Inhibitors
Pyridines
Pyrroles
Recombinant Proteins
JAK2 protein, human
Janus Kinase 2