Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type I receptor kinase

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• 作者：Maddeboina Krishnaiah ; Cheng Hua Jin^&dagger ; ; Yhun Yhong Sheen ; Dae-Kee Kim ; ^{dkkim@ewha.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TGF-β ; ALK5 inhibitor ; Fibrosis ; Cancer ; Kinase assay
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5228-5231
• 全文大小：592 K

文摘

To further optimize a clinical candidate rong class="boldFont">5rong> (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles rong class="boldFont">19arong>–rong class="boldFont">lrong> have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles rong class="boldFont">19hrong>–rong class="boldFont">lrong> displayed the similar level of potency to that of rong class="boldFont">5rong> against both ALK5 (IC₅₀ = 7.68–13.70 nM) and p38α MAP kinase (IC₅₀ = 1240–3370 nM). Among them, rong class="boldFont">19jrong> inhibited ALK5 with IC₅₀ value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.