Discovery and development of a novel N-(3-bromophenyl)-{[(phenylcarbamoyl)amino]methyl}-N-hydroxythiophene-2-carboximidamide indoleamine 2,3-dioxygenase inhibitor using knowledge-based drug design

Eur J Med Chem. 2022 Feb 5:229:114043. doi: 10.1016/j.ejmech.2021.114043. Epub 2021 Dec 8.

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.

Keywords: Cancer immunotherapy; Indoleamine 2,3-dioxygenase; Knowledge-based drug design.

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / therapeutic use
  • Half-Life
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Mice
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Transplantation, Heterologous

Substances

  • Amides
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Thiophenes