Innate immunity is the first and immediate line of defense against invading endogenous or exogenous pathogens. Here, the NOD-like receptor family pyrin domain containing 3 (NLRP3) acts as a sensor that detects a broad range of danger signals [1]. Upon its activation, pro-caspase-1 is cleaved to form mature caspase-1, leading to subsequent release of IL-1 ß and Gasdermin N-terminal fragments, and ultimately to inflammation and pyroptosis [2].
Aberrant activation of NLRP3 due to e.g. persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated period syndrome (CAPS), Parkinson’s disease, gout and numerous others [3]. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however its mode of action was only elucidated later [4]. Based on MCC950 second-generation inhibitors were developed, aiming to overcome some liabilities such as moderate potency and drug induced liver injury (DILI) [5]. During the optimization of these (second-generation) inhibitors, conformational studies lead to the identification of novel macrocycles [6]. Here we report the discovery and optimization of this class of NLRP3 inhibitors.

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[3] J. Shannon et al., J. Parkinson's Disease, 2022, 12, S113; Chen et al.; J. Neuroinflammation, 2021, 18, 84.
[4] Coll et al., Nature Medicine, 2015, 21,248. Coll et al., Nat. Chem Biol, 2019, 15, 556.
[5] McBride C et al., J. Med. Chem., 2022, 65, 14721.
[6] Cooper et al., WO2021032588, 2021; R.B. Kargbo, ACS Med. Chem. Lett.; 2021, 12, 1075.