Design and Synthesis of 5‐Aryl‐substituted Phenylpyrimidine‐2,4‐diamine Derivatives as Novel Mer and Tyro3 Kinase Inhibitors

5‐Aryl‐substituted (piperdin‐4‐yl)pyrimidine‐2,4‐diamine derivatives were synthesized and their inhibitory activities were evaluated against TAM kinase (Tyro3, Axl, Mer), respectively. Detailed SAR studies on the fifth position of pyrimidine could lead to the discovery of potent and selective TAM ki...

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Bibliographic Details
Published in:Bulletin of the Korean Chemical Society 2021, 42(2), , pp.206-211
Main Authors: Kim, Yeonji, Lee, Kyung Won, Yeom, Hyesu, Kim, Miok, Lee, Yeon Kyung, Lee, Joo‐Youn, Hwang, Jong Yeon, Min, Youngki, Ryu, Do Hyun, Lee, Chang Hoon, Cho, Sung Yun
Format: Article
Language:English
Subjects:
Anticancer agent
Axl inhibitor
Mer inhibitor
TAM
Tyro3 inhibitor
화학
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Summary:5‐Aryl‐substituted (piperdin‐4‐yl)pyrimidine‐2,4‐diamine derivatives were synthesized and their inhibitory activities were evaluated against TAM kinase (Tyro3, Axl, Mer), respectively. Detailed SAR studies on the fifth position of pyrimidine could lead to the discovery of potent and selective TAM kinase inhibitor. Compounds 6f, 7b, and 7f exhibited potent inhibitory activity and excellent selectivity toward Axl, Tyro3 and Mer kinases. Molecular docking studies corroborated that slight changes of substituents induced dramatic structural change of Met596, 623, 674 backbone carbonyl and amide in the hinge region of Axl, Tyro3, Mer, and resulted in different binding poses of 6f, 7b, and 7f, respectively. It was identified as a strong possibility to control selectivity by structural modification of phenyl substituents of pyrimidine as a new class of TAM kinase inhibitors. Mer kinase inhibitor
ISSN:1229-5949
0253-2964
1229-5949
DOI:10.1002/bkcs.12167