Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors. Issue 2 (15th January 2020)

• Record Type: Journal Article
• Authors: Ren, Jing; Shi, Wei; Zhao, Damin; Wang, Qinglin; Chang, Xiayun; He, Xiangyi; Wang, Xiaojin; Gao, Yong; Lu, Peng; Zhang, Xiquan; Xu, Hongjiang; Zhang, Yinsheng
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 2(2020)
• Publication Date: 2020-01-15
• Subjects: BTK -- JAK3 -- Dual inhibitor -- Benzoxaborole -- Pyrimidine -- Hematological -- Autoimmune diseases; ATP adenosine triphosphate -- HATU O-(7-aza-1H-benzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium hexafluorophosphate -- DIPEA N, N-diisopropylethylamine -- DME 1, 2-dimethoxyethane -- DMAP N, N-dimethylaminopyridine -- DMF N, N-dimethylformamide -- DMSO dimethylsulfoxide -- THF tetrahydrofuran -- TFA trifluoroacetic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115236
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A dominant pharmacophore re-combination strategy was successfully used to design kinases inhibitors. A series of boron-containing compounds were synthesized, and some of them exhibited significant inhibitory activity against BTK and JAK3 with both IC50 values below 1 nM. Several compounds have shown 10-folds more active in the enzyme and cell-based assays than a known active compound, ibrutinib and CC292. Abstract: Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are very promising targets for hematological malignancies and autoimmune diseases. In recent years, a few compounds have been approved as a marketed medicine, and several are undergoing clinical trials. By recombining the dominant backbone of known active compounds, constructing a foused library, and screening a broad panel of kinases, we found a class of compounds with dual activities of anti-BTK and anti-JAK3. Some of the compounds have shown 10-folds more active in the enzyme and cell-based assays than a known active compound. Furthermore, liver microsome stability experiments show that these compounds have better stability than ibrutinib. These explorations offered new clues to discover benzoxaborole fragment and pyrimidine scaffold as more effective BTK and JAK3 dual inhibitors.