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

  • Bioorg Med Chem Lett. 2012 May 15;22(10):3392-7. doi: 10.1016/j.bmcl.2012.04.013.
Mark L Boys  1 ,  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 Gowan ,  Elena 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
Affiliations
  • 1. Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. [email protected]
PMID: 22542194 DOI: 10.1016/j.bmcl.2012.04.013
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.

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