2. Academic Validation
  3. Discovery of 1-Amino-1 H-imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitors

Discovery of 1-Amino-1 H-imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitors

  • J Med Chem. 2021 Nov 11;64(21):16242-16270. doi: 10.1021/acs.jmedchem.1c01559.
Chunhua Ma 1,  Qingyun Li 1,  Minghao Zhao 1,  Goujie Fan 1,  Jie Zhao 1,  Dandan Zhang 1,  Shouning Yang 1,  Shuting Zhang 1,  Dingding Gao 2,  Longfei Mao 1 3,  Liang Zhu 1,  Wei Li 1 3,  Guiqing Xu 1,  Yuqin Jiang 1,  Qingjie Ding 1
Affiliations

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 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3 Henan Zhiwei Biomedicine Co., Ltd., Xinxiang, Henan 453007, China.
PMID: 34672559 DOI: 10.1021/acs.jmedchem.1c01559
Abstract

Bruton's tyrosine kinase (Btk) inhibitors suppressing the aberrant activation of Btk have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent Btk inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel Btk inhibitors carrying 1-amino-1H-imidazole-5-carboxamide as a hinge binder. The most potent Btk Inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1H-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

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