Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors.
ChemMedChem
; 12(17): 1449-1457, 2017 09 07.
Article
in En
| MEDLINE
| ID: mdl-28703484
ABSTRACT
Insulin-secretory sulfonylureas are widely used, cost-effective treatments for typeâ
2 diabetes (T2D). However, pancreatic ß-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-1ß, has been linked to pancreatic ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreas
/
Sulfonylurea Compounds
/
Inflammasomes
/
NLR Family, Pyrin Domain-Containing 3 Protein
/
Hypoglycemic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
ChemMedChem
Journal subject:
FARMACOLOGIA
/
QUIMICA
Year:
2017
Document type:
Article
Affiliation country:
Australia