Bioorganic and Medicinal Chemistry Letters p. 3052 - 3059 (2016)
Update date:2022-08-11
Topics:
Zou, Yi
Xiao, Jianhu
Tu, Zhengchao
Zhang, Yingyi
Yao, Kun
Luo, Minghao
Ding, Ke
Zhang, Yihua
Lai, Yisheng
A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07 μM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.
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Doi:10.1246/bcsj.20140378
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