Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors |
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Affiliation: | 1. College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian 116044, PR China;2. Department of Hematology, Institute of Respiratory Diseases, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China;1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China;2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;4. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;5. School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China;1. College of Laboratory Medicine, College of Pharmacy, Dalian Medical University, Dalian, PR China;2. Clinical Laboratory, Department of Clinical Laboratory, Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, 210009, PR China;2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050, PR China |
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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. |
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Keywords: | BTK JAK3 Dual inhibitor Benzoxaborole Pyrimidine Hematological Autoimmune diseases ATP" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" adenosine triphosphate HATU" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" O-(7-aza-1" },{" #name" :" italic" ," _" :" H" },{" #name" :" __text__" ," _" :" -benzotriazol-1-yl)-" },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ′," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ′-tetramethyluronium hexafluorophosphate DIPEA" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -diisopropylethylamine DME" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" 1,2-dimethoxyethane DMAP" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -dimethylaminopyridine DMF" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -dimethylformamide DMSO" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" dimethylsulfoxide THF" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" tetrahydrofuran TFA" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" trifluoroacetic acid |
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