Novel Macrocyclic NLRP3 Inhibitors

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.