Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis.
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.
Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Amit
A
Sarswat
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.
Ewa
E
Wasilewski
Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Sai K
SK
Chakka
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.
Angelica M
AM
Bello
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Andrew V
AV
Caprariello
Centre for Molecular Design and Preformulations, and Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Chithra M
CM
Muthuramu
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Peter K
PK
Stys
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.
Shannon E
SE
Dunn
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.
Lakshmi P
LP
Kotra
D000818:Animals; D001921:Brain / Q000473:pathology; D020134:Catalytic Domain; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy; D004660:Encephalitis / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009187:Myelitis / Q000139:chemically induced; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D013116:Spinal Cord / Q000473:pathology; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
C000625358:3-(2-(1H-imidazol-1-yl)ethyl)-5,5-dimethylhydantoin; C000625359:3-(2-(1H-tetrazol-5-yl)ethyl)-5,5-dimethylimidazolidine-2,4-dione; D004791:Enzyme Inhibitors; D006827:Hydantoins; D007093:Imidazoles; D007527:Isoenzymes; D018696:Neuroprotective Agents; D013777:Tetrazoles; D003471:Cuprizone; D006867:Hydrolases; C019723:arginine deiminase
Citrullination; Hydantoins; Multiple sclerosis; Neurodegeneration; Protein-arginine deiminase; Structure-activity relationship