Velcicky, Juraj, Janser, Philipp, Gommermann, Nina, Brenneisen, Silke, Ilic, Slavica, Vangrevelinghe, Eric, Stiefl, Nikolaus, Boettcher, Andreas, Malinverni, Claire, Dawson, Janet, Desrayaud, Sandrine, Beltz, Karen, Hinniger, Alexandra, Dekker, Carien, Farady, Christopher and Mackay, Angela (2024) Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors. Journal of medicinal chemistry. ISSN 1520-4804

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-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.

Item Type:	Article
Date Deposited:	20 Jan 2024 00:45
Last Modified:	20 Jan 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52289