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
  • 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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