Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1, 5-a]pyrazine core featuring 3-position bicyclic ring substitutes. Issue 17 (1st September 2020)

• Record Type: Journal Article
• Authors: Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; Gao, Xiaolei; Wang, James; Babu Boga, Sobhana; Alhassan, Abdul-Basit; Yu, Wensheng; Selyutin, Oleg; Yu, Younong; Anand, Rajan; Xu, Jiayi; Kelly, Joseph; Duffy, Joseph L.; Liu, Shilan; Yang, Chundao; Wu, Hao; Cai, Jiaqiang; Bennett, Chad; Maloney, Kevin M.; Tyagarajan, Sriram; Gao, Ying-Duo; Fischmann, Thierry O.; Presland, Jeremy; Mansueto, My; Xu, Zangwei; Leccese, Erica; Zhang-Hoover, Jie; Knemeyer, Ian; Garlisi, Charles G.; Stivers, Peter; Brandish, Philip E.; Hicks, Alexandra; Kim, Ronald; Kozlowski, Joseph A.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 17(2020)
• Publication Date: 2020-09-01
• Subjects: Bruton's Tyrosine Kinase -- Structure based drug design -- Kinase selectivity -- Rat CIA model -- X-ray crystal structure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127390
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.