Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis

Bioorg Med Chem. 2017 May 1;25(9):2643-2656. doi: 10.1016/j.bmc.2017.03.006. Epub 2017 Mar 6.

Abstract

Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5-membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes-two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model.

Keywords: Citrullination; Hydantoins; Multiple sclerosis; Neurodegeneration; Protein-arginine deiminase; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Catalytic Domain
  • Cuprizone
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / drug therapy
  • Encephalitis / chemically induced
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Half-Life
  • Humans
  • Hydantoins / administration & dosage
  • Hydantoins / chemistry
  • Hydantoins / pharmacokinetics
  • Hydantoins / therapeutic use*
  • Hydrolases / antagonists & inhibitors*
  • Imidazoles / administration & dosage
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use*
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Multiple Sclerosis / drug therapy*
  • Myelitis / chemically induced
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / therapeutic use
  • Spinal Cord / pathology
  • Tetrazoles / administration & dosage
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacokinetics
  • Tetrazoles / therapeutic use*

Substances

  • 3-(2-(1H-imidazol-1-yl)ethyl)-5,5-dimethylhydantoin
  • 3-(2-(1H-tetrazol-5-yl)ethyl)-5,5-dimethylimidazolidine-2,4-dione
  • Enzyme Inhibitors
  • Hydantoins
  • Imidazoles
  • Isoenzymes
  • Neuroprotective Agents
  • Tetrazoles
  • Cuprizone
  • Hydrolases
  • arginine deiminase