Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors

Eur J Med Chem. 2020 Jul 15:198:112354. doi: 10.1016/j.ejmech.2020.112354. Epub 2020 Apr 29.

Abstract

Inhibition of transforming growth factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model.

Keywords: ALK5; Antitumor activity; TGF-β inhibitor.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Fibrosis / drug therapy*
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • NIH 3T3 Cells
  • Neoplasms / drug therapy*
  • Neoplasms, Experimental / drug therapy
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacokinetics
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Receptor, Transforming Growth Factor-beta Type I