Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / pharmacokinetics
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Aniline Compounds / pharmacology
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Aniline Compounds / toxicity
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Animals
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Antifibrinolytic Agents / chemical synthesis*
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Antifibrinolytic Agents / pharmacokinetics
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Antifibrinolytic Agents / pharmacology
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Antifibrinolytic Agents / toxicity
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / toxicity
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Biological Availability
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Drug Discovery
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HEK293 Cells
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Humans
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Immunotherapy
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / toxicity
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
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Triazoles / toxicity
Substances
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Aniline Compounds
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Antifibrinolytic Agents
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Receptors, Transforming Growth Factor beta
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Triazoles
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vactosertib
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, rat