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

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

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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