Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

Mark L. Boys, Feng Bian, James B. Kramer, Christopher L. Chio, Xiao Dan Ren, Huifen Chen, Stephen D. Barrett, Karen E. Sexton, Donna M. Iula, Gary F. Filzen, Maria N. Nguyen, Paul Angell, Victoria L. Downs, Zhi Wang, Neil Raheja, Edmund L. Ellsworth, Stephen Fakhoury, Larry D. Bratton, Paul R. Keller, Richard GowanElena M. Drummond, Samarendra N. Maiti, Mostofa A. Hena, Leroy Lu, Patrick McConnell, John D. Knafels, Venkataraman Thanabal, Fang Sun, Diane Alessi, Ann McCarthy, Erli Zhang, Barry C. Finzel, Sneha Patel, Susan M. Ciotti, Rone Eisma, N. A. Payne, Richard B. Gilbertsen, Catherine R. Kostlan, David J. Pocalyko, Deepak S. Lala

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

Original languageEnglish (US)
Pages (from-to)3392-3397
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number10
DOIs
StatePublished - May 15 2012

Keywords

  • Activin receptor-like Kinase 5
  • Dermal scarring
  • Topical
  • Transforming growth factor beta
  • Wound repair

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    Boys, M. L., Bian, F., Kramer, J. B., Chio, C. L., Ren, X. D., Chen, H., Barrett, S. D., Sexton, K. E., Iula, D. M., Filzen, G. F., Nguyen, M. N., Angell, P., Downs, V. L., Wang, Z., Raheja, N., Ellsworth, E. L., Fakhoury, S., Bratton, L. D., Keller, P. R., ... Lala, D. S. (2012). Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring. Bioorganic and Medicinal Chemistry Letters, 22(10), 3392-3397. https://doi.org/10.1016/j.bmcl.2012.04.013