Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton's tyrosine kinase (BTK) inhibitors.
A novel series of BTK inhibitors bearing thieno[3,2-c]pyridin-4-amine framework as the core scaffold were designed, synthesized and well characterized. In this paper, twenty one compounds displayed variant inhibitory activities against BTK in vitro, and compound 14 g showed the most potent inhibitory activity against BTK enzyme, with the IC50 value of 12.8 nM. Moreover, compounds 14 g displayed relatively good kinase selectivity and was subsequently evaluated in vivo for profiling its PK properties. This work identified the thieno[3,2-c]pyridin-4-amine derivatives as novel BTK inhibitors and verified the value of thieno[3,2-c]pyridin-4-amine scaffold in drug design.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Xinge
X
Zhao
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an 710061, PR China.
Minhang
M
Xin
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Yazhou
Y
Wang
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
Wei
W
Huang
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Qiu
Q
Jin
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Feng
F
Tang
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Gang
G
Wu
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Yong
Y
Zhao
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China. Electronic address: 1020030692@cpu.edu.cn.
Hua
H
Xiang
D015195:Drug Design; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors
BTK inhibitors; Inhibitory activity; Kinase selectivity; Thieno[3,2-c]pyridin-4-amine