2. Academic Validation
  3. Novel Macrocyclic NLRP3 Inhibitors

Novel Macrocyclic NLRP3 Inhibitors

  • J Med Chem. 2024 Dec 12;67(23):20911-20932. doi: 10.1021/acs.jmedchem.4c01376.
Stefanie Mesch 1,  Jonathan Shannon 2,  David Miller 3,  Angus MacLeod 3,  Léa Bouché 1,  Heather J Johnston 2,  Kim Matthews 3,  Axel Paehler 1,  Stuart Best 2,  Wolfgang Guba 1,  Thomas Alanine 2,  Reena Halai 3,  Lorna Charge 2,  Samantha Garside 2,  Stephen Thom 2,  Celia Incerti-Pradillos 2,  Christopher McPherson 2,  Jokin Carrillo 2,  Steve St-Gallay 2,  Pierre Rigo 1,  Sonja Schlicht 1,  Alan G Hendrick 1,  Christian Lerner 1,  Luca Piali 1,  Julie Blaising 1,  Eva Z Mracsko 1,  Georg Jaeschke 1,  Matthew A Cooper 3
Affiliations

Affiliations

  • 1 F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel CH-4070, Switzerland.
  • 2 Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, U.K.
  • 3 Inflazome Ltd., 6 Falcon Way, Shire Park, Welwyn Garden City AL7 1TW, U.K.
PMID: 39585325 DOI: 10.1021/acs.jmedchem.4c01376
Abstract

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous Others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later. Based on MCC950, second-generation inhibitors were developed, aiming to overcome some liabilities such as moderate potency and drug induced liver injury. During the optimization of these (second-generation) inhibitors, conformational studies led to the design of novel macrocycles. Here we report the discovery and optimization of this class of NLRP3 inhibitors.

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