2. Academic Validation
  3. Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity

Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity

  • J Med Chem. 2025 Feb 27;68(4):4848-4887. doi: 10.1021/acs.jmedchem.4c03108.
Oscar Mammoliti 1,  Rodrigo Carbajo 2,  Laura Perez-Benito 1,  Xiaodi Yu 3,  Marion L C Prieri 1,  Leonardo Bontempi 1,  Sofie Embrechts 1,  Ine Paesmans 1,  Michela Bassi 1,  Anindya Bhattacharya 4,  Santiago Cañellas 2,  Saskia De Hoog 1,  Samuël Demin 1,  Harrie J M Gijsen 1,  Geerwin Hache 1,  Tom Jacobs 1,  Soufyan Jerhaoui 1,  Joseph Leenaerts 1,  Ferdinand H Lutter 1,  Michel Mahieu 1,  Rosalie Matico 3,  Robyn Miller 3,  Daniel Oehlrich 1,  Mathieu Perrier 1,  Pavel Ryabchuk 1,  Wim Schepens 1,  Sujata Sharma 3,  Marijke Somers 1,  Javier Suarez 3,  Michel Surkyn 1,  Nina Van Opdenbosch 5,  Tinne Verhulst 1,  Astrid Bottelbergs 1
Affiliations

Affiliations

  • 1 Janssen Pharmaceutica NV, A Johnson & Johnson Company, Turnhoutseweg 30, Beerse 2340, Belgium.
  • 2 Janssen-Cilag S.A., A Johnson & Johnson Company, C/Jarama 75A, 45007 Toledo, Spain.
  • 3 Janssen Research & Development, LLC, A Johnson & Johnson Company, Spring House, Pennsylvania 19477, United States.
  • 4 Janssen Research & Development, LLC, A Johnson & Johnson Company, 3210 Merryfield Row, San Diego, California 92121-1126, United States.
  • 5 Janssen Interventional Oncology, Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 39932543 DOI: 10.1021/acs.jmedchem.4c03108
Abstract

NLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1β, and Pyroptosis, a regulated cell death. Mounting evidence associates excessive NLRP3 activation to neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases. Thus, NLRP3 inhibitors could potentially provide therapeutic benefit for these disorders. We describe here the evolution of inhibitors relying on a pyridazine-based motif for their key interactions with NLRP3. A Cryo-EM structure helped optimizing protein-ligand complementarity. Subsequently, conformational NMR studies pointed the efforts toward 5,6-bicyclic cores that allowed a balance between brain penetration and undesirable properties, such as hERG inhibition. The effort culminated in compound 19, which showed moderate (mouse) to good (rat) brain penetration and was active at low dose in an LPS challenge model. Importantly, an earlier compound was active in a central neuroinflammation model providing a valuable proof of concept for NLRP3 inhibition.

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