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

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• 作者：Mark L. Boys^a ; ^&dagger ; ; ^{mark.boys@arraybiopharma.com} ; Feng Bian^a ; James B. Kramer^a ; Christopher L. Chio^a ; Xiao-Dan Ren^a ; Huifen Chen^a ; Stephen D. Barrett^a ; Karen E. Sexton^a ; Donna M. Iula^a ; Gary F. Filzen^a ; ^&Dagger ; ; Maria N. Nguyen^a ; Paul Angell^a ; Victoria L. Downs^a ; Zhi Wang^a ; Neil Raheja^a ; Edmund L. Ellsworth^a ; Stephen Fakhoury^a ; Larry D. Bratton^a ; Paul R. Keller^a ; Richard Gowan^a ; Elena M. Drummond^a ; Samarendra N. Maiti^b ; Mostofa A. Hena^b ; Leroy Lu^b ; Patrick McConnell^a ; John D. Knafels^a ; Venkataraman Thanabal^a ; Fang Sun^a ; Diane Alessi^a ; Ann McCarthy^a ; Erli Zhang^a ; Barry C. Finzel^a ; Sneha Patel^a ; Susan M. Ciotti^a ; Rone Eisma^a ; N.A. Payne^a ; Richard B. Gilbertsen^a ; Catherine R. Kostlan^a ; David J. Pocalyko^a ; Deepak S. Lala^a ; ^§ ; ; ^{dlala@vitaerx.com}
• 关键词：Activin receptor-like Kinase 5 ; Transforming growth factor beta ; Topical ; Dermal scarring ; Wound repair
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3392-3397
• 文件大小：1749 K

摘要

A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGF尾 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 TGF尾 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.