Dapansutrile, an oral NLRP3 inhibitor, shows broad anti-inflammatory promise from gout to aging

Chronic, low-grade inflammation underlies many age-related diseases, yet current anti-inflammatory drugs such as NSAIDs carry cardiovascular, kidney, and brain risks. The NLRP3 inflammasome, which drives maturation of IL-1β and IL-18, is a prime target. MCC950, the best-known inhibitor, has been limited by potential liver toxicity. Dapansutrile (OLT1177) is an oral β-sulfonyl nitrile compound positioned as a better-tolerated alternative.

This narrative review synthesizes preclinical and clinical literature on dapansutrile. Mechanistically, it binds the NLRP3 NACHT domain, suppressing ATPase activity and oligomerization. It reduces NLRP3 binding to ASC and caspase-1 without affecting AIM2 or NLRC4 inflammasomes, and without altering upstream signals such as K+ efflux. It also limits neutrophil, T-cell, and mast-cell infiltration, inhibits caspase-1-mediated GSDMD cleavage (pyroptosis), and reduces ROS and STAT3 phosphorylation.

In gout, the phase 2a trial (29 per-protocol patients, 100-2000 mg/day) showed target-joint pain reductions of 82-89% by day 7, with significant IL-6 declines. IL-1β trended downward but not significantly, and IL-6 served as a proxy. In HFrEF patients, 14 days of treatment raised LVEF from 31.5% to 36.5% and extended exercise time by 46 seconds. Mouse studies showed a 71% smaller infarct size after ischemia-reperfusion and preserved contractile reserve after myocardial infarction. APP/PS1 Alzheimer's mice fed OLT1177 for three months had reversed cognitive deficits and lower plaque burden. In Parkinson's models it crossed the blood-brain barrier, enhanced microglial autophagy, and protected dopaminergic neurons. Combined with lonafarnib, it extended survival in progeria mice and reduced senescence and SASP markers. With anti-PD-1 therapy, it enhanced CD8+ T-cell activity and tumor control in mice. Further benefits were reported in osteoarthritis, periodontitis, colitis, liver injury, and EAE models.

Together, these findings suggest a versatile, orally active, selective anti-inflammatory with a favorable safety profile and potential for combination regimens, including with AI-guided drug pairing. The review stresses the need for better CNS delivery.

Caveats are substantial. Most evidence comes from rodent models, and human data are limited to small, short, early-phase trials. Some mouse models may not reflect chronic disease, efficacy in advanced Alzheimer's is unknown, and effects on other NLRP family members or pyrin are unclear. The review is narrative rather than systematic, so selection bias is possible.