Format

Send to

Choose Destination
ChemMedChem. 2017 Sep 7;12(17):1449-1457. doi: 10.1002/cmdc.201700270. Epub 2017 Aug 4.

Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, St. Lucia, Brisbane, Queensland, 4072, Australia.
2
Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales, 2010, Australia.
3
Inflazome Ltd., The Tower, Trinity TEC, Pearse Street, Dublin, 2, Ireland.

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.

KEYWORDS:

NLRP3; diabetes; inflammasomes; inflammation; multi-target

PMID:
28703484
DOI:
10.1002/cmdc.201700270
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center