NT-0796

NT-0796 is an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome and a prodrug form of NDT-19795.¹ It selectively inhibits NLRP3 over NLR family CARD domain-containing protein 4 (NLRC4) at 3 nM, as well as a panel of 121 other receptors at 10 µM, but does inhibit the serotonin (5-HT) receptor subtype 5-HT_2B by 90% at 10 µM. NT-0796 inhibits LPS- and ATP-induced IL-1β release in isolated human peripheral blood mononuclear cells (PBMCs) and whole blood (IC₅₀s = 0.32 and 6.8 nM, respectively), however, it does not affect LPS-induced TNF-α or IL-6 release in isolated human PBMCs (IC₅₀s = >2 µM for both), indicating NLRP3 selectivity. It decreases body weight, food intake, and plasma levels of total cholesterol, HDL, and proprotein convertase subtilisin kexin type 9 (PCSK9) in a model of high-fat diet-induced obesity using transgenic mice expressing human carboxylesterase-1 (CES1), the enzyme that converts NT-0796 to NDT-19795, when administered at a dose of 100 mg/kg three times per day.²

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1. Harrison, D., Billinton, A., Bock, M.G., et al. Discovery of clinical candidate NT-0796, a brain-penetrant and highly potent NLRP3 inflammasome inhibitor for neuroinflammatory disorders. J. Med. Chem. 66(21), 14897-14911 (2023).

2. Thornton, P., Reader, V., Digby, Z., et al. Reversal of high fat diet-induced obesity, systemic inflammation, and astrogliosis by the NLRP3 inflammasome inhibitors NT-0249 and NT-0796. J. Pharmacol. Exp. Ther. 388(3), 813-826 (2024).