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.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / pathology
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Catalytic Domain
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Cuprizone
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Demyelinating Diseases / chemically induced
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Demyelinating Diseases / drug therapy
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Encephalitis / chemically induced
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / therapeutic use*
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Female
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Half-Life
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Humans
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Hydantoins / administration & dosage
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Hydantoins / chemistry
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Hydantoins / pharmacokinetics
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Hydantoins / therapeutic use*
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Hydrolases / antagonists & inhibitors*
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Imidazoles / administration & dosage
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / therapeutic use*
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Isoenzymes / antagonists & inhibitors
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Male
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Multiple Sclerosis / drug therapy*
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Myelitis / chemically induced
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / therapeutic use
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Spinal Cord / pathology
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Tetrazoles / administration & dosage
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Tetrazoles / chemistry
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Tetrazoles / pharmacokinetics
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Tetrazoles / therapeutic use*
Substances
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3-(2-(1H-imidazol-1-yl)ethyl)-5,5-dimethylhydantoin
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3-(2-(1H-tetrazol-5-yl)ethyl)-5,5-dimethylimidazolidine-2,4-dione
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Enzyme Inhibitors
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Hydantoins
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Imidazoles
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Isoenzymes
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Neuroprotective Agents
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Tetrazoles
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Cuprizone
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Hydrolases
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arginine deiminase