Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors
Résumé
NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1β (IL-1β), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease. In this study, the synthesis of acrylamide derivatives and their pharmaco-toxicological evaluation as potential inhibitors of NLRP3-dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL-1β release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2-(2-chlorobenzyl)-N-(4-sulfamoylphenethyl)acrylamide, which was able to concentration-dependently inhibit NLRP3 ATPase with an IC50 value of 74 μm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.
Mots clés
Acrylamide
acrylamide derivatives
Animals
Cell Survival
Cells
Cultured
Dose-Response Relationship
Drug
Drug Design
Humans
Inflammasomes
inflammation
Interleukin-1beta
Macrophages
Mice
Inbred C57BL
Models
Molecular
Molecular Structure
NLR Family
Pyrin Domain-Containing 3 Protein
pyroptosis
Structure-Activity Relationship