Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia

作者：Liu, He; Qu, Menghua; Xu, Lina; Han, Xu; Wang, Chanyuan; Shu, Xiaohong; Yao, Jihong; Liu, Kexin; Peng, Jinyong; Li, Yanxia; Ma, Xiaodong^*

来源：European Journal of Medicinal Chemistry, 2017, 135: 60-69.

DOI：10.1016/j.ejmech.2017.04.037

• Leukemia
• BTK
• Inhibitor
• Pyrimidine
• Sulfonamide

A new series of diphenylpyrimidine derivatives (SFA-DPPYs) were synthesized by introducing a functional sulfonamide into the C-2 aniline moiety of pyrimidine template, and then were biologically evaluated as potent Bruton's tyrosine kinase (BTK) inhibitors. Among these molecules, inhibitors 10c, 10i, 10j and 10k displayed high potency against the BTK enzyme, with IC50 values of 1.18 nM, 0.92 nM, 0.42 nM and 1.05 nM, respectively. In particular, compound 10c could remarkably inhibit the proliferation of the B lymphoma cell lines at concentrations of 6.49 mu M (Ramos cells) and 13.2 mu M (Raji cells), and was stronger than the novel agent spebrutinib. In addition, the inhibitory potency toward the normal PBMC cells showed that inhibitor 10c possesses low cell cytotoxicity. All these explorations indicated that molecule 10c could serve as a valuable inhibitor for B-cell lymphoblastic leukemia treatment. 2017 Elsevier Masson SAS.

• 出版日期2017-7-28
• 单位大连医科大学