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ID: ALA4028813

Journal: Bioorg Med Chem

Title: Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis.

Authors: Sarswat A, Wasilewski E, Chakka SK, Bello AM, Caprariello AV, Muthuramu CM, Stys PK, Dunn SE, Kotra LP.

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.

CiteXplore: 28341402

DOI: 10.1016/j.bmc.2017.03.006