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.
Enzyme Inhibitors/therapeutic use , Multiple Sclerosis/drug therapy , Neurodegenerative Diseases/drug therapy , Protein-Arginine Deiminases/antagonists & inhibitors , Animals , Brain/pathology , Cell Movement/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mice , Motor Disorders/drug therapy , Multiple Sclerosis/pathology , Neurodegenerative Diseases/pathology , T-Lymphocytes/pathology , Treatment Outcome
