Dapansutrile

Dapansutrile is a β-sulfonyl nitrile inhibitor of the NLRP3 inflammasome that inhibits the release of IL-1β and decreases caspase-1 levels in LPS-stimulated J774A.1 murine macrophages, human monocyte derived macrophages (HMDMs), and primary human blood neutrophils without affecting TNF-α release.¹ It is selective for NLRP3 over NLRP4 and AIM2 inflammasomes at concentrations up to 100 μM. Dapansutrile inhibits ASC oligomerization and NLRP3 association with caspase-1 and ASC in LPS- and nigericin-stimulated J774A.1 cells. In vivo, Dapansutrile reduces myeloperoxidase (MPO), CXCL1, and IL-6 levels in peritoneal fluid as well as IL-1β levels in liver, lung, spleen, and skeletal muscle in a mouse model of LPS-induced systemic inflammation. It decreases oxidized glutathione and oxaloacetate and increases reduced glutathione, α-ketoglutarate, and citrate levels, markers of oxidative metabolism, in muscle in a mouse model of LPS-induced systemic inflammation. Dapansutrile also reduces IL-1β release in blood monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), an autoinflammatory disorder characterized by gain-of-function mutations in NLRP3.

1.Marchetti, C., Swartzwelter, B., Gamboni, F., et al.OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammationProc. Natl. Acad. Sci. USA115(7)E1530-E1539(2018)