The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs). The NLR family is most commonly classified according to their N-terminal domain, falling into one of four subfamilies; NLRA, NLRB, NLRC and NLRP. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic responses.

The NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor (ASC), and an effector (caspase-1). NLRP3 is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals, and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. What’s more, the NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. Following published research, many NLRP3 inflammasome inhibitors can inhibit cytokine release via disruption of the NLRP3 inflammasome pathway. The most widely studied NLRP3 inhibitor is MCC950 (CP-456773; CRID3).

Here, we will introduce another NLRP3 inflammasome inhibitor, NDT-30805.

NDT-30805, a triazolopyrimidinone derivative, is a potent and selective NLRP3 inflammasome inhibitor. NDT-30805 possesses high solubility and very low membrane permeability. Its advantage is uncharged at physiological pH. Meanwhile, its disadvantages are high protein binding and low permeability, which in part may derive from the high lipophilicity and aromatic character. Importantly, NDT-30805 inhibits IL-1β release in PBMCs with an IC₅₀ of 13 nM. Therefore, NDT-30805 has the potential for the research of inflammation and innate immunity.

All in all, NDT-30805, a potent and selective NLRP3 inflammasome inhibitor, exhibits anti-inflammatory activity.

Reference:

Swanson KV, et, al. Nat Rev Immunol. 2019 Aug;19(8):477-489.