Discovery of N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavai

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• 作者：Cheng Hua Jin ; Maddeboina Krishnaiah ; Domalapally Sreenu ; Vura B. Subrahmanyam ; Kota S. Rao ; Hwa Jeong Lee ; So-Jung Park ; Hyun-Ju Park ; Kiho Lee ; Yhun Yhong Sheen ; Dae-Kee Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4213-4238
• 全文大小：790K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-尾 type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC₅₀ value of 0.013 渭M in a kinase assay and with IC₅₀ values of 0.0165 and 0.0121 渭M in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b路HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng 脳 h/mL and maximum plasma concentration (C_max) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.