Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors

James R Hill, Rebecca C Coll, Nancy Sue, Janet C Reid, Jennifer Dou, Caroline L Holley, Ruby Pelingon, Joshua B Dickinson, Trevor J Biden, Kate Schroder, Matthew A Cooper, Avril A B Robertson

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1449-1457
Number of pages9
JournalChemMedChem
Volume12
Issue number17
Early online date13 Jul 2017
DOIs
Publication statusPublished - 07 Sep 2017
Externally publishedYes

Bibliographical note

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • Animals
  • Cell Line
  • Cells, Cultured
  • Diabetes Mellitus, Type 2/drug therapy
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents/chemistry
  • Inflammasomes/antagonists & inhibitors
  • Insulin/immunology
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
  • Pancreas/cytology
  • Sulfonylurea Compounds/chemistry

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    Hill, J. R., Coll, R. C., Sue, N., Reid, J. C., Dou, J., Holley, C. L., Pelingon, R., Dickinson, J. B., Biden, T. J., Schroder, K., Cooper, M. A., & Robertson, A. A. B. (2017). Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors. ChemMedChem, 12(17), 1449-1457. https://doi.org/10.1002/cmdc.201700270