The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

Tony Siu*, Sathyajith E. Kumarasinghe, Michael D. Altman, Matthew Katcher, Alan Northrup, Catherine White, Craig Rosenstein, Anjili Mathur, Lin Xu, Grace Chan, Eric Bachman, Melaney Bouthillette, Christopher J. Dinsmore, C. Gary Marshall, Jonathan R. Young

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    4 Scopus citations


    This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

    Original languageEnglish (US)
    Pages (from-to)1466-1471
    Number of pages6
    JournalBioorganic and Medicinal Chemistry Letters
    Issue number6
    StatePublished - Mar 15 2014


    • JAK2
    • Kinase partition index
    • Kinase selectivity
    • Kinases
    • Ligand binding affinity
    • Molecular modeling
    • Water interaction

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry


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