The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1β and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.
Keywords: AMS-17; Computational chemistry; Inflammasome; Inflammation; Microglia; Molecular mechanics; NLRP3; Phamacophore modeling; Quantum mechanics; Sulfonylurea.
Published by Elsevier Ltd.