Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis

Abstract

In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 ± 1.56 μM. Selective inhibition of the NLRP3 inflammasome induced IL-1β release by this compound was also confirmed using mouse bone-marrow-derived macrophages and LPS-challenged mice in vivo. Furthermore, immunoprecipitation study revealed that JC-171 interfered with NLRP3/ASC interaction induced by LPS/ATP stimulation. More importantly, JC-171 treatment delayed the progression and reduced the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in both prophylactic and therapeutic settings. This coincided with blocking of IL-1β production and a pathogenic Th17 response. Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…A rationally designed small‐molecule inhibitor of NLRP3, the hydroxyl sulfonamide analogue JC‐171, has been reported to dose‐dependently inhibit NLRP3‐mediated IL‐1β production through disruption of NLRP3‐ASC interaction in both cellular and animal models of multiple sclerosis (EAE) …”

“…116 A rationally designed small-molecule inhibitor of NLRP3, the hydroxyl sulfonamide analogue JC-171, has been reported to dose-dependently inhibit NLRP3mediated IL-1β production through disruption of NLRP3-ASC interaction in both cellular and animal models of multiple sclerosis (EAE). 117 The ATPase activity of NLRP3 is crucial for selfoligomerization of NLRP3 and its association with ASC, which activates the inflammasome complex. 118,119 Many NLRP3 inhibitors, such as 3,4-methylenedioxyβ-nitrostyrene (MNS) and BAY 11-7082, contain a common structural feature, α,β-unsaturated carbonyl group called Michael acceptors (Table 1).…”

Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 inflammasome Activity and Activating Nrf2 Signaling

“…Bixin is a natural carotenoid with multiple bioactivities. Previous studies have shown that bixin has antiin ammation, anti-tumor, and anti-oxidative effects [28][29][30][31][32]. Xu Z et al [19] have found that bixin attenuates cardiac injury by inhibiting in ammation and oxidative stress in a high-fat-diet mouse model.…”

“…The TXNIP/NLRP3 in ammasome plays a key role in the pathogenesis of various diseases [30,32,34,35]. Chen W et al [9] have indicated that minocycline improves diabetic retinopathy by inhibiting the TXNIP/NLRP3 in ammasome pathway, and Vitamin D3 attenuates diabetic retinopathy by inhibiting high-glucose-induced ROS/TXNIP/NLRP3 in ammasome pathway [36].…”

Role of Inflammasomes in Neuroimmune and Neurodegenerative Diseases: A Systematic Review

“…The upstream factors and downstream effectors of inflammasomes are attractive therapeutic targets in the context of EAE/MS. JC-171, a hydroxyl sulfonamide analogue, which is a selective NLRP3 inflammasome inhibitor, has been shown to exhibit preventive and therapeutic effects in the EAE setting [ 92 ]. In a study by Coll et al [ 93 ], MCC950 (a diarylsulfonylurea-containing compound that inhibits IL-1 β ) was shown to specifically inhibit canonical and noncanonical NLRP3 activation in EAE.…”