Journal of medicinal chemistry · 2024
Novel Macrocyclic NLRP3 Inhibitors.
СтатьяНазвание и аннотация: Перевод в очереди
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Mesch Stefanie, Shannon Jonathan, Miller David, MacLeod Angus, Bouché Léa, Johnston Heather J, Matthews Kim, Paehler Axel, Best Stuart, Guba Wolfgang, Alanine Thomas, Halai Reena, Charge Lorna, Garside Samantha, Thom Stephen, Incerti-Pradillos Celia, McPherson Christopher, Carrillo Jokin, St-Gallay Steve, Rigo Pierre, Schlicht Sonja, Hendrick Alan G, Lerner Christian, Piali Luca, Blaising Julie, Mracsko Eva Z, Jaeschke Georg, Cooper Matthew A
Аннотация
Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. 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 their mode of action was only elucidated later. Based on MCC950, second-generation inhibitors were developed, aiming to overcome some liabilities such as moderate potency and drug induced liver injury. During the optimization of these (second-generation) inhibitors, conformational studies led to the design of novel macrocycles. Here we report the discovery and optimization of this class of NLRP3 inhibitors.