Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties.

Abstract

In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

• Authors: Xiaojing Wang, James Barbosa, Peter Blomgren, Meire C Bremer, Jacob Chen, James J Crawford, Wei Deng, Liming Dong, Charles Eigenbrot, Steve Gallion, Jonathon Hau, Huiyong Hu, Adam R Johnson, Arna Katewa, Jeffrey E Kropf, Seung H Lee, Lichuan Liu, Joseph W Lubach, Jen Macaluso, Pat Maciejewski, Scott A Mitchell, Daniel F Ortwine, Julie DiPaolo, Karin Reif, Heleen Scheerens, Aaron Schmitt, Harvey Wong, Jin-Ming Xiong, Jianjun Xu, Zhongdong Zhao, Fusheng Zhou, Kevin S Currie, Wendy B Young
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 8 Issue 6 Pg. 608-613 (Jun 08 2017) ISSN: 1948-5875 [Print] United States
• PMID: 28626519 (Publication Type: Journal Article)