Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors

NLRP3 is a molecular sensor recognizing a wide range
of danger
signals. Its activation leads to the assembly of an inflammasome that
allows for activation of caspase-1 and subsequent maturation of IL-1β
and IL-18, as well as cleavage of Gasdermin-d and pyroptotic
cell death. The NLRP3 inflammasome has been implicated in a plethora
of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer’s
disease, and cancer. In this publication, we describe the discovery
of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening.
The hit (1) could be optimized into an advanced compound NP3–562 demonstrating excellent potency in human whole
blood and full inhibition of IL-1β release in a mouse acute
peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3–562 bound to the NLRP3 NACHT domain revealed a
unique binding mode as compared to the known sulfonylurea-based inhibitors.
In addition, NP3–562 shows also a good overall
development profile.