Sulfonylureas as concomitant insulin secretagogues and NLRP3 inflammasome inhibitors

Hill, James R., Coll, Rebecca C., Sue, Nancy, Reid, Janet C., Dou, Jennifer, Holley, Caroline L., Pelingon, Ruby, Dickinson, Joshua B., Biden, Trevor J., Schroder, Kate, Cooper, Matthew A. and Robertson, Avril A. B. (2017) Sulfonylureas as concomitant insulin secretagogues and NLRP3 inflammasome inhibitors. ChemMedChem, 12 17: 1449-1457. doi:10.1002/cmdc.201700270

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Author Hill, James R.
Coll, Rebecca C.
Sue, Nancy
Reid, Janet C.
Dou, Jennifer
Holley, Caroline L.
Pelingon, Ruby
Dickinson, Joshua B.
Biden, Trevor J.
Schroder, Kate
Cooper, Matthew A.
Robertson, Avril A. B.
Title Sulfonylureas as concomitant insulin secretagogues and NLRP3 inflammasome inhibitors
Journal name ChemMedChem   Check publisher's open access policy
ISSN 1860-7187
1860-7179
Publication date 2017-08-04
Year available 2017
Sub-type Article (original research)
DOI 10.1002/cmdc.201700270
Open Access Status File (Author Post-print)
Volume 12
Issue 17
Start page 1449
End page 1457
Total pages 10
Place of publication Weinheim, Germany
Publisher Wiley
Language eng
Abstract Insulin-secretory sulfonylureas are widely used, cost-effective treatments for type 2 diabetes (T2D). However, pancreatic β-cells are continually depleted as T2D progresses, thereby rendering the sulfonylurea drug class ineffective in controlling glycaemia. Dysregulation of the innate immune system via activation of the NLRP3 inflammasome, and the consequent production of interleukin-1β, has been linked to pancreatic β-cell death and multiple inflammatory complications of T2D disease. One proposed strategy for treating T2D is the use of sulfonylurea insulin secretagogues that are also NLRP3 inhibitors. We report the synthesis and biological evaluation of nine sulfonylureas that inhibit NLRP3 activation in murine bone-marrow- derived macrophages in a potent, dose-dependent manner. Six of these compounds inhibited NLRP3 at nanomolar concentrations and can also stimulate insulin secretion from a murine pancreatic cell line (MIN6). These novel compounds possess unprecedented dual modes of action, paving the way for a new generation of sulfonylureas that may be useful as therapeutic candidates and/or tool compounds in T2D and its associated inflammatory complications.
Keyword Diabetes
Inflammasomes
Inflammation
Multi-target
NLRP3
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID AISRF07840
APP1086786 | APP1059354
Research Scholarship | Honours Scholarship
FT130100361
Research Advancement Award
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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