2. Academic Validation
  3. Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors

Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors

  • J Med Chem. 2024 Jan 25;67(2):1544-1562. doi: 10.1021/acs.jmedchem.3c02098.
Juraj Velcicky 1,  Philipp Janser 1,  Nina Gommermann 1,  Silke Brenneisen 1,  Slavica Ilic 1,  Eric Vangrevelinghe 1,  Nikolaus Stiefl 1,  Andreas Boettcher 1,  Christelle Arnold 1,  Claire Malinverni 1,  Janet Dawson 1,  Renata Murgasova 1,  Sandrine Desrayaud 1,  Karen Beltz 1,  Alexandra Hinniger 1,  Carien Dekker 1,  Christopher J Farady 1,  Angela Mackay 1
Affiliations

Affiliation

  • 1 Novartis Biomedical Research, CH-4002 Basel, Switzerland.
PMID: 38175811 DOI: 10.1021/acs.jmedchem.3c02098
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.

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