Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes
In: Bioorganicmedicinal chemistry letters, Jg. 30 (2020-05-08), Heft 17
Online
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Zugriff:
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
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Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes
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Autor/in / Beteiligte Person: | Cai, Jiaqiang ; Xu, Jiayi ; Gao, Ying-Duo ; Wang James J-S ; Guiadeen, Deodial ; Yu, Wensheng ; Krikorian, Arto D. ; Kozlowski, Joseph A. ; Zhang-Hoover, Jie ; Wu, Hao ; Sobhana Babu Boga ; Presland, Jeremy ; Bennett, Chad ; Gao, Xiaolei ; Garlisi, Charles G. ; Maloney, Kevin M. ; Liu, Shilan ; My Sam Mansueto ; Kelly, Joseph ; Alhassan, Abdul-Basit ; Hicks, Alexandra ; Anand, Rajan ; Liu, Jian ; Leccese, Erica ; Brandish, Philip E. ; Kim, Ronald M. ; Stivers, Peter ; Duffy, Joseph L. ; Tyagarajan, Sriram ; Fischmann, Thierry O. ; Selyutin, Oleg ; Yu, Younong ; Knemeyer, Ian ; Xu, Zangwei ; Yang, Chundao |
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Zeitschrift: | Bioorganicmedicinal chemistry letters, Jg. 30 (2020-05-08), Heft 17 |
Veröffentlichung: | 2020 |
Medientyp: | unknown |
ISSN: | 1464-3405 (print) |
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