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
  • 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: [email protected].
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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