Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2

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Abstract

Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.

References and notes (30)

  • L. Song et al.

    JAK-STAT Signalling

    K. Shuai et al.

    Nat. Rev. Immunol.

    (2003)
    K. Ghoreschi et al.

    J. Immunol. Rev.

    (2009)
  • Kontzias, A.; Laurence, A.; Gadina, M.; O’Shea, J. J. F1000 Medicine Reports, 2012, doi:...
  • M. Zak et al.

    J. Med. Chem.

    (2012)
  • J.J. Kulagowski et al.

    J. Med. Chem.

    (2012)
  • I.B. McInnes et al.

    Nat. Rev. Immunol.

    (2007)
  • R.F. Van Vollenhoven

    Nat. Rev. Rheumatol.

    (2009)
  • P.C. Heinrich et al.

    J. Biochem.

    (1998)
  • J.E. Darnell

    Science

    (1997)
  • J.S. Smolen et al.

    Lancet

    (2008)
  • R. Fleischmann et al.

    Arthritis Rheum.

    (2012)
  • Q. Lin et al.

    Org. Lett.

    (2009)
  • (a)A related small molecule JAK1/2 inhibitor (INCB028050/LY3009104) is being evaluated for rheumatoid...J.S. Fridman et al.

    J. Immunol.

    (2010)
  • E. Parganas et al.

    Cell

    (1998)
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