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

J Med Chem. 2014 May 22;57(10):4213-38. doi: 10.1021/jm500115w. Epub 2014 May 13.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / pharmacology
  • Aniline Compounds / toxicity
  • Animals
  • Antifibrinolytic Agents / chemical synthesis*
  • Antifibrinolytic Agents / pharmacokinetics
  • Antifibrinolytic Agents / pharmacology
  • Antifibrinolytic Agents / toxicity
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Biological Availability
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Immunotherapy
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / toxicity
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology
  • Triazoles / toxicity

Substances

  • Aniline Compounds
  • Antifibrinolytic Agents
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptors, Transforming Growth Factor beta
  • Triazoles
  • vactosertib
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, rat