Discovery of 1‑Amino‑1 H ‑imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitors
2021
academicJournal
Zugriff:
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-1 H -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-1 H -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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Discovery of 1‑Amino‑1 H ‑imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitors
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Autor/in / Beteiligte Person: | Chunhua Ma (5792261) ; Qingyun Li (845696) ; Minghao Zhao (9136910) ; Goujie Fan (11591456) ; Jie Zhao (49409) ; Dandan Zhang (228849) ; Shouning Yang (8656365) ; Shuting Zhang (436486) ; Dingding Gao (7236311) ; Longfei Mao (9683276) ; Liang Zhu (172992) ; Wei Li (7081) ; Guiqing Xu (148569) ; Yuqin Jiang (6618434) ; Qingjie Ding (1846105) |
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Veröffentlichung: | 2021 |
Medientyp: | academicJournal |
DOI: | 10.1021/acs.jmedchem.1c01559.s003 |
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