Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor

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Abstract

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

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Acknowledgement

The authors thank Dr. Nancy Delaet for her feedback on the content of this Letter.

References and notes (21)

  • Experimental details on biochemical and cellular assays can be found in the Supplementary data...
  • The JNK3 isoform was the only one available to us for crystallography during this drug discovery...
  • N.M. Davies
  • M.Y. Chu-Moyer et al.

    Bioorg. Med. Chem. Lett.

    (2002)
  • H.-P. Hauber et al.

    Inflamm. Allergy: Drug Targets

    (2010)
    R.H. Gomer et al.

    Expert Opin. Invest. Drugs

    (2010)
    R.M. du Bois

    Nat. Rev. Drug Discov.

    (2010)
  • G. Raghu et al.

    Am. J. Respir. Crit. Care Med.

    (2011)
  • Plantevin Krenitsky, V.; Nadolny, L.; Sahasrabudhe, K.; Ayala, L.; Delgado, M.; Clareen, S.; Hilgraf, R.; Albers, R.;...
  • S. Tanemura et al.

    Curr. Enz. Inhib.

    (2010)
  • P.R. Eynott et al.

    Br. J. Pharmacol.

    (2003)
    M.H. de Borst et al.

    J. Pharmacol. Exp. Ther.

    (2009)
    J. Kluwe et al.

    Gastroenterology

    (2010)
    W. Wu et al.

    Circulation

    (2011)
    M.H. De Borst et al.

    J. Pathol.

    (2007)
  • M.A. Siddiqui et al.

    J. Med. Chem.

    (2010)
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