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1.
Bioorg Med Chem ; 25(9): 2643-2656, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28341402

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.


Subject(s)
Enzyme Inhibitors/therapeutic use , Hydantoins/therapeutic use , Hydrolases/antagonists & inhibitors , Imidazoles/therapeutic use , Multiple Sclerosis/drug therapy , Tetrazoles/therapeutic use , Animals , Brain/pathology , Catalytic Domain , Cuprizone , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Encephalitis/chemically induced , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Half-Life , Humans , Hydantoins/administration & dosage , Hydantoins/chemistry , Hydantoins/pharmacokinetics , Imidazoles/administration & dosage , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Isoenzymes/antagonists & inhibitors , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Myelitis/chemically induced , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/therapeutic use , Spinal Cord/pathology , Tetrazoles/administration & dosage , Tetrazoles/chemistry , Tetrazoles/pharmacokinetics
2.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 7): o1818, 2010 Jun 26.
Article in English | MEDLINE | ID: mdl-21588025

ABSTRACT

The asymmetric unit cell of the title compound, C(18)H(18)N(2)O, contains four molecules. In the crystal structure, an inter-molecular N-H⋯N hydrogen bond helps to establish the packing.

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