Table 2.
Overview of pharmacological compounds targeting inflammasome signaling
| Compounds | Benefit (+)/detriment (−) | Neurodegenerative disease model |
|---|---|---|
| Caspase‐1 inhibitors | ||
| VX‐765 and VX‐740 | (−) No further development after phase II clinical trial for use in epilepsy and psoriasis (Mangan et al, 2018) |
Alzheimer disease (Flores et al, 2018) EAE (Mckenzie et al, 2018) |
| NLRP3 inflammasome inhibitors | ||
| Sulfonylurea‐based compounds | ||
| Glyburide |
(+) Specific for NLRP3 inflammasomes; significantly delays LPS‐induced mortality (Lamkanfi et al, 2009) (−) High dosage required (Marchetti et al, 2014); cardiovascular side effects (Riddle, 2003) |
TBI (Simard et al, 2012) Ischemic stroke (Simard et al, 2012) |
| CP‐412,245 and CP‐424,174 | (+) Oral administration of CP‐424,174 selectively blocks IL‐1 production in mice (Perregaux et al, 2001) | |
| CRID1 and CRID2 | (−) No in vivo evidence | |
| MCC950 (also known as CRID3 or CP‐456,773) |
(+) NLRP3 inflammasome specific (Coll et al, 2015); inhibits NLRP3 activation by all known stimuli (Mangan et al, 2018) (−) Precise molecular target unknown |
Alzheimer disease (Dempsey et al, 2017) EAE (Coll et al, 2015) TBI (Ismael et al, 2018a; Xu et al, 2018) Stroke (Ismael et al, 2018b; Ren et al, 2018) |
| 16673‐34‐0 | (+) Lacks cyclohexylurea group responsible for hypoglycemic activity; prevents NLRP‐mediated myocardial injury (Marchetti et al, 2014) | |
| Hybrid molecules (combining MCC950 and glyburide) | (−) Moderately effective at inhibiting NLRP3 compared to MCC950 (Hill et al, 2017) | |
| Fenamate classes of NSAIDs | ||
| Flufenamic and mefenamic acid |
(+) Inhibits NLRP3 by blocking VRACs (Daniels et al, 2016) (−) Lack of specificity, inhibits multiple inflammatory nodes (Daniels et al, 2016) |
Alzheimer disease (Daniels et al, 2016) |
| Michael acceptors | ||
| Parthenolide | (−) No suitable pharmacological properties (Baldwin et al, 2016); inhibits NF‐κB‐dependent signaling (Saadane et al, 2007) | Stroke (Dong et al, 2013) |
| BAY 11‐7082 | (−) Not specific; inhibits NF‐κB‐dependent signaling (Lee et al, 2012) | TBI (Irrera et al, 2017) |
| 3,4‐methylenedioxy‐β‐nitrostyrene (MNS) | (−) Modest potency (Baldwin et al, 2016) | |
| Acrylate and acrylamide derivatives (ex. IFN58, IFN39) | (+) Oral administration of IFN39 alleviates DNBS‐induced colitis in rats (Cocco et al, 2017) | |
| Novel boron compound series | ||
| NBC13 | (+) Significantly decreases LPS‐induced IL‐1β production in vivo (Baldwin et al, 2017) | |
| Other NLRP3 inhibitors | ||
| Fc11a‐2 | (+) In vivo efficacy in DSS‐induced colitis (Liu et al, 2013b) | |
| CY‐09 | (+) Therapeutic effect in mouse models of CAPS and type 2 diabetes (Jiang et al, 2017) | |
| JC‐171 | (+) Treatment effective in EAE in both prophylactic and therapeutic settings (Guo et al, 2017) | EAE (Guo et al, 2017) |
| OLT‐177 | (+) No adverse effects in preliminary clinical testing of healthy humans (Marchetti et al, 2018) | |
| β‐hydroxybutyrate (BHB) | (−) Not specific for NLRP3; can inhibit HDACs (Youm et al, 2015) | |
| GSDMD inhibitors | ||
| Antabuse | (+) Efficacious in sepsis models (preprint: Hu et al, 2018) | |
| Necrosulfonamide | (+) Efficacious in sepsis models (Rathkey et al, 2018) | |