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Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 May 11; Vol. 60 (9), pp. 3656-3671. Date of Electronic Publication: 2017 Apr 24. - Publication Year :
- 2017
-
Abstract
- Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.
- Subjects :
- Acrylates pharmacokinetics
Acrylates pharmacology
Animals
Energy Transfer
Male
Mice
Mice, Inbred C57BL
Rats
Rats, Sprague-Dawley
Acrylates therapeutic use
Inflammasomes drug effects
Inflammatory Bowel Diseases drug therapy
NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28410442
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01624