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TitleDiscovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 4, Page 4848-4887, Year 2025
Publish dateFeb 27, 2025
AuthorsOscar Mammoliti / Rodrigo Carbajo / Laura Perez-Benito / Xiaodi Yu / Marion L C Prieri / Leonardo Bontempi / Sofie Embrechts / Ine Paesmans / Michela Bassi / Anindya Bhattacharya / Santiago Cañellas / Saskia De Hoog / Samuël Demin / Harrie J M Gijsen / Geerwin Hache / Tom Jacobs / Soufyan Jerhaoui / Joseph Leenaerts / Ferdinand H Lutter / Michel Mahieu / Rosalie Matico / Robyn Miller / Daniel Oehlrich / Mathieu Perrier / Pavel Ryabchuk / Wim Schepens / Sujata Sharma / Marijke Somers / Javier Suarez / Michel Surkyn / Nina Van Opdenbosch / Tinne Verhulst / Astrid Bottelbergs /
PubMed AbstractNLRP3 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 ...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 , 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.
External linksJ Med Chem / PubMed:39932543
MethodsEM (single particle)
Resolution2.9 - 3.93 Å
Structure data

48263

9mgy

EMDB-48263, PDB-9mgy:
Cryo-EM structure of Human NLRP3 complex with compound 1
Method: EM (single particle) / Resolution: 2.9 Å

48288

9mie

EMDB-48288, PDB-9mie:
Human NLRP3 complex with compound 2 in the closed hexamer
Method: EM (single particle) / Resolution: 3.93 Å

48289

9mig

EMDB-48289, PDB-9mig:
Cryo-EM structure of Human NLRP3 complex with compound 3
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

PDB-1blr:
NMR SOLUTION STRUCTURE OF HUMAN CELLULAR RETINOIC ACID BINDING PROTEIN-TYPE II, 22 STRUCTURES

ChemComp-HOH:
WATER

PDB-1blp:
STRUCTURAL BASIS FOR THE INACTIVATION OF THE P54 MUTANT OF BETA-LACTAMASE FROM STAPHYLOCOCCUS AUREUS PC1

PDB-1blq:
STRUCTURE AND INTERACTION SITE OF THE REGULATORY DOMAIN OF TROPONIN-C WHEN COMPLEXED WITH THE 96-148 REGION OF TROPONIN-I, NMR, 29 STRUCTURES

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / NLRP3 / cryo-EM / small molecule inhibitor / inflammasome

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