Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors

Xuewu Liang; Yongxue Huang; Jie Zang; Qianwen Gao; Binghe Wang; Wenfang Xu; Yingjie Zhang

doi:10.1016/j.bmc.2016.04.030

Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors

Bioorg Med Chem. 2016 Jun 15;24(12):2660-72. doi: 10.1016/j.bmc.2016.04.030. Epub 2016 Apr 20.

Authors

Xuewu Liang¹, Yongxue Huang¹, Jie Zang¹, Qianwen Gao¹, Binghe Wang², Wenfang Xu¹, Yingjie Zhang³

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, PR China.
² Georgia Research Alliance Eminent Scholar in Drug Discovery, Department of Chemistry, Georgia State University, United States. Electronic address: chebw@langate.gsu.edu.
³ Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.

PMID: 27137359
DOI: 10.1016/j.bmc.2016.04.030

Abstract

JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.

Keywords: 4-Aminopyrazole; Inhibitors; JAKs; Kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Drug Design
HeLa Cells
Humans
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / metabolism
Janus Kinases / antagonists & inhibitors*
Janus Kinases / metabolism
Molecular Docking Simulation
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*

Substances

3-cyclohexyl-3-(4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
JAK2 protein, human
Janus Kinase 2
Janus Kinases