1. Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors
- Author
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Velcicky, Juraj, Janser, Philipp, Gommermann, Nina, Brenneisen, Silke, Ilic, Slavica, Vangrevelinghe, Eric, Stiefl, Nikolaus, Boettcher, Andreas, Arnold, Christelle, Malinverni, Claire, Dawson, Janet, Murgasova, Renata, Desrayaud, Sandrine, Beltz, Karen, Hinniger, Alexandra, Dekker, Carien, Farady, Christopher J., and Mackay, Angela
- Abstract
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-dand 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 NP3–562demonstrating 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 NP3–562bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3–562shows also a good overall development profile.
- Published
- 2024
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