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

  • ACS Med Chem Lett. 2017 May 3;8(6):608-613. doi: 10.1021/acsmedchemlett.7b00103.
Xiaojing Wang  1 ,  James Barbosa  2 ,  Peter Blomgren  2 ,  Meire C Bremer  1 ,  Jacob Chen  1 ,  James J Crawford  1 ,  Wei Deng  3 ,  Liming Dong  3 ,  Charles Eigenbrot  1 ,  Steve Gallion  2 ,  Jonathon Hau  1 ,  Huiyong Hu  1 ,  Adam R Johnson  1 ,  Arna Katewa  1 ,  Jeffrey E Kropf  2 ,  Seung H Lee  2 ,  Lichuan Liu  1 ,  Joseph W Lubach  1 ,  Jen Macaluso  2 ,  Pat Maciejewski  2 ,  Scott A Mitchell  2 ,  Daniel F Ortwine  1 ,  Julie DiPaolo  2 ,  Karin Reif  1 ,  Heleen Scheerens  1 ,  Aaron Schmitt  2 ,  Harvey Wong  1 ,  Jin-Ming Xiong  2 ,  Jianjun Xu  2 ,  Zhongdong Zhao  2 ,  Fusheng Zhou  3 ,  Kevin S Currie  2 ,  Wendy B Young  1
Affiliations
  • 1. Genentech, Inc., Research and Early Development, 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Gilead Sciences (formerly CGI Pharmaceuticals), 199 East Blaine Street, Seattle, Washington 98102, United States.
  • 3. ChemPartner, No. 1 Building, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai, China 201203.
PMID: 28626519 DOI: 10.1021/acsmedchemlett.7b00103
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.

Keywords
Btk; G-744; Kinase inhibitor; Lupus; Rheumatoid arthritis.
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