Novel Macrocyclic NLRP3 Inhibitors
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.
Authors
- Celia A. Incerti‐Pradillos
- Jokin Carrillo (ORCID: https://orcid.org/0000-0001-9867-5628)
- Christopher McPherson
- Jonathan Shannon (ORCID: https://orcid.org/0009-0002-8275-6268)
- Wolfgang Guba (ORCID: https://orcid.org/0000-0002-3285-5957)
- Axel Paehler
- Léa Bouché (ORCID: https://orcid.org/0000-0001-8523-812X)
- Thomas A. Alanine (ORCID: https://orcid.org/0000-0002-3349-0726)
- Heather J. Johnston (ORCID: https://orcid.org/0009-0005-1707-7850)
- Angus M. MacLeod
- C. Lerner (ORCID: https://orcid.org/0009-0001-4235-3387)
- Susan C. Garside
- Stephen Thom
- Stephen A. St-Gallay (ORCID: https://orcid.org/0000-0003-3904-007X)
- Eva Zsuszsanna Mracskó
- Philippe Rigo (ORCID: https://orcid.org/0000-0002-2508-5851)
- Reena Halai
- Stefanie Mesch (ORCID: https://orcid.org/0009-0009-3821-2838)
- Alan G. Hendrick (ORCID: https://orcid.org/0000-0002-8604-0462)
- Matthew A. Cooper (ORCID: https://orcid.org/0000-0003-3147-3460)
- Georg Jaeschke (ORCID: https://orcid.org/0000-0002-9393-6822)
- Luca Piali
- Julie Blaising (ORCID: https://orcid.org/0000-0002-3367-6184)
- D.O. Miller (ORCID: https://orcid.org/0000-0003-1017-3979)
- Sonja Schlicht
- Kim L. Matthews
- Stuart Best
- Lorna Charge
Institutions
- Roche (Switzerland) (CH)
- Signature Research (United States) (US)
- Deutsche Telekom (United Kingdom) (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01376
- Citations
- 4
- Primary Topic
- Synthesis of heterocyclic compounds
- Type
- article
- Field-Weighted Citation Impact
- 1.00