2. Academic Validation
  3. Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis

Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis

  • J Med Chem. 2017 Nov 9;60(21):8876-8887. doi: 10.1021/acs.jmedchem.7b01102.
Elizabeth J Curiel Tejeda 1,  Angelica M Bello 1 2,  Ewa Wasilewski 1 2,  Adam Koebel 1 2,  Shannon Dunn 2 3,  Lakshmi P Kotra 1 2 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
  • 2 Centre for Molecular Design and Preformulations, Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7, Canada.
  • 3 Department of Immunology, University of Toronto , Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
  • 4 Multi-Organ Transplant Program, Toronto General Hospital , 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
PMID: 29045782 DOI: 10.1021/acs.jmedchem.7b01102
Abstract

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD Enzymes. Among the various heterocycles investigated, compound 23, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose IP. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS.

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