2. Academic Validation
  3. Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome

Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome

  • J Med Chem. 2024 Dec 12;67(23):20780-20798. doi: 10.1021/acs.jmedchem.4c02350.
Angela Mackay 1,  Juraj Velcicky 1,  Nina Gommermann 1,  Henri Mattes 1,  Philipp Janser 1,  Michael Wright 1,  Celine Dubois 1,  Silke Brenneisen 1,  Slavica Ilic 1,  Eric Vangrevelinghe 1,  Nikolaus Stiefl 1,  Andreas Boettcher 1,  Michel Schoenboerner 1,  Melanie Vogelsanger 1,  Sophie Muller-Bentz 1,  Marion Kamke 1,  Joelle Rubert 1,  Muriel Kauffmann 1,  Sandrine Desrayaud 1,  Markus Trunzer 1,  Honnappa Srinivas 1,  Alexandra Hinniger 1,  Nicole von Burg 1,  Karen Beltz 1,  Carien Dekker 1,  Christopher J Farady 1
Affiliations

Affiliation

  • 1 Novartis Biomedical Research, CH-4002 Basel, Switzerland.
PMID: 39574318 DOI: 10.1021/acs.jmedchem.4c02350
Abstract

Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer's disease and Cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign. The scaffold, exemplified by lead molecule NP3-253, has excellent potency and physicochemical and pharmacokinetic properties, including good brain penetration. The establishment of pharmacokinetic/pharmacodynamic relationships in the periphery and central nervous system in mechanistic models facilitates the use of NP3-253 as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models.

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