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 Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent
| Autor: | Kota S Rao, Yhun Yhong Sheen, Maddeboina Krishnaiah, Kiho Lee, Dae-Kee Kim, Hwa Jeong Lee, Cheng Hua Jin, Hyun-Ju Park, So-Jung Park, Vura Bala Subrahmanyam, Domalapally Sreenu |
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| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
Receptor Transforming Growth Factor-beta Type I Administration Oral Biological Availability Antineoplastic Agents Protein Serine-Threonine Kinases Structure-Activity Relationship Drug Discovery Animals Humans Moiety Structure–activity relationship Luciferase Receptor Protein Kinase Inhibitors IC50 Aniline Compounds Kinase Chemistry Triazoles Antifibrinolytic Agents Rats Bioavailability HaCaT HEK293 Cells Molecular Medicine Immunotherapy Receptors Transforming Growth Factor beta |
| Zdroj: | Journal of Medicinal Chemistry. 57:4213-4238 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm500115w |
| Popis: | 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-β 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 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM 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·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b. |
| Databáze: | OpenAIRE |
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