Structure-activity relationship investigation for imidazopyrazole-3-carboxamide derivatives as novel selective inhibitors of Bruton's tyrosine kinase

Eur J Med Chem. 2021 Dec 5:225:113724. doi: 10.1016/j.ejmech.2021.113724.

Dandan Zhang ¹, Guiqing Xu ¹, Jie Zhao ¹, Yue Wang ¹, Xiaofang Wu ², Xing He ¹, Wei Li ¹, Shuting Zhang ¹, Shouning Yang ¹, Chunhua Ma ³, Yuqin Jiang ⁴, Qingjie Ding ⁵

Affiliations

1 Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China.
2 Hang Zhou City of Quality and Technical Supervision and Testing Institute, Hangzhou, Zhejiang, 310019, China.
3 Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China. Electronic address: 2016007@htu.edu.cn.
4 Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China. Electronic address: jiangyuqin@htu.cn.
5 Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China. Electronic address: qjding@yahoo.com.

PMID: 34391034 DOI: 10.1016/j.ejmech.2021.113724

Abstract

Btk (Bruton's tyrosine kinase) inhibitors are the most promising drugs for the treatment of hematological tumors. A high selectivity of Btk inhibitors ensures reduced side effects from off-targeting. Accordingly, here, based on Zanubrutinib, we designed and synthesized a new range of imidazopyrazole-3-carboxamide derivatives as novel Btk inhibitors that retained the amide group for improved selectivity. These compounds revealed potent inhibitory activity against Btk in vitro. Remarkably, compounds 12a (IC₅₀ 5.2 nM) and 18a (IC₅₀ 4.9 nM) possessed the highest kinase selectivity. Both of these effectively inhibited the auto-phosphorylation of Btk, blocked the cell cycle in G0/G1 phase, and induced Apoptosis in the TMD8 cells. In a TMD8 cells xenograft model, a twice-daily dose of compound 12a at 25 mg/kg and a thrice-daily dose of compound 18a at 15 mg/kg significantly suppressed the tumor growth without obvious toxicity. Collectively, 12a and 18a are the potential selective Btk inhibitors that can be developed further.

Keywords

Antiproliferation; BTK; Imidazopyrazole; Inhibitors; Selectivity.

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