2. Academic Validation
  3. Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis

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.
Amit Sarswat 1,  Ewa Wasilewski 2,  Sai K Chakka 1,  Angelica M Bello 2,  Andrew V Caprariello 3,  Chithra M Muthuramu 1,  Peter K Stys 3,  Shannon E Dunn 4,  Lakshmi P Kotra 5
Affiliations

Affiliations

  • 1 Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.
  • 2 Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario M5S 3M2, Canada.
  • 3 Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • 4 Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Immunology, University of Toronto, and Women's College Research Institute, Toronto, Ontario, M5S 1B2, Canada.
  • 5 Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario M5S 3M2, Canada. Electronic address: lkotra@uhnres.utoronto.ca.
PMID: 28341402 DOI: 10.1016/j.bmc.2017.03.006
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.

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