Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor

Agarwal, Sameer; Pethani, Jignesh P.; Shah, Hardik; Vyas, Vismit; Sasane, Santosh; Bhavsar, Harsh; Bandyopadhyay, Debdutta; Giri, Poonam; Viswanathan, Kasinath; Jain, Mukul; Sharma, R. P.

doi:10.1016/j.bmcl.2020.127571

Cited by 22 publications

(18 citation statements)

References 23 publications

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“…Recently published structure-activity relationships concerning diarylsulfonylurea-based NLRP3 inhibitors revealed the intact western indacene moiety of CRID3/MCC950 to be crucial for biological activity, and hence for target binding. On the other hand, structural alterations on the eastern sulfonamide part were better tolerated (Hill et al, 2017(Hill et al, , 2020bAgarwal et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Development of Fluorescent and Biotin Probes Targeting NLRP3

et al. 2021

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Extracellular signals drive the nucleation of the NLRP3 inflammasome which leads to the release of cytokines and causes inflammatory events. Hence, the inflammasome has gained enormous momentum in biomedical basic research. The detailed mechanisms of inflammasome generation and regulation remain to be elucidated. Our study was directed toward the design, convergent synthesis, and initial biochemical evaluation of activity-based probes addressing NLRP3. For this purpose, probes were assembled from a CRID3/MCC950-related NLRP3-binding unit, a linker portion and a coumarin 343 fluorophore or biotin. The affinity of our probes to NLRP3 was demonstrated through SPR measurements and their cellular activity was confirmed by reduction of the interleukin 1β release from stimulated bone marrow-derived macrophages. The initial characterizations of NLRP3-targeting probes highlighted the coumarin probe 2 as a suitable tool compound for the cellular and biochemical analysis of the NLRP3 inflammasome.

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Section: Resultsmentioning

confidence: 99%

Development of Fluorescent and Biotin Probes Targeting NLRP3

et al. 2021

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“…(2019) proposed that mitochondrial transporters ABCb7 and ABCb10 are the pharmacological targets of CP-453773; although this hypothesis has been proven incorrect, they found that undifferentiated THP1 cells can serve as a reliable and simplified model for investigating NLRP3 inflammasomes ( Guzova et al., 2019 ). MCC950 was found to increase serum liver enzyme levels in a phase II clinical trial in rheumatoid arthritis; hence, it was not further developed ( Agarwal, Pethani, et al., 2020 ). Abdullaha et al.…”

Section: Specific Inhibitors Of Nlrp3 Inflammasomementioning

confidence: 99%

“… Agarwal et al. (2020) reported that thiazolo-alkenyl sulfonylurea derivative 7 inhibited the activation of NLRP3 by inhibiting ASC oligomerisation ( Agarwal, Pethani, et al., 2020 ).…”

Section: Specific Inhibitors Of Nlrp3 Inflammasomementioning

confidence: 99%

“… Agarwal et al. (2020) reported that thiazolo-alkenyl sulfonylurea derivative 7 inhibited the activation of NLRP3 by inhibiting ASC oligomerisation ( Agarwal, Pethani, et al., 2020 ). Unlike other ASC inhibitors, thiazolo-alkenyl sulfonylurea derivative 7 does not affect the AIM2 inflammasome, but its inhibitory effects on CYP2C8 and CYP2C9 limit its in vivo application, despite its good pharmacokinetic properties ( Agarwal, Pethani, et al., 2020 ).…”

Section: Specific Inhibitors Of Nlrp3 Inflammasomementioning

confidence: 99%

“…Based on findings reported by Agarwal et al. (2020) , compounds generated after structurally modifying the sulfonylurea part of MCC950 also demonstrated inhibitory effects on the NLRP3 inflammasome ( Agarwal, Sasane, et al., 2020 ); hence, it was possible to develop novel NLRP3 inflammasome inhibitors based on the sulfonylurea structure.…”

Section: Specific Inhibitors Of Nlrp3 Inflammasomementioning

confidence: 99%

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The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets

et al. 2021

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Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-β, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.

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