Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors

• Published in: ChemMedChem Vol. 12; no. 17; pp. 1449 - 1457
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.09.2017; Wiley Subscription Services, Inc
• Subjects: Animals; Beta cells; Blood glucose; Bone marrow; Cell activation; Cell death; Cell Line; Cells, Cultured; Chemistry, Medicinal; Complications; diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - immunology; HEK293 Cells; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Immune system; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - immunology; inflammation; Inhibitors; Innate immunity; Insulin; Insulin - immunology; Insulin secretion; Interleukin 1; Life Sciences & Biomedicine; Macrophages; Mice, Inbred C57BL; multi-target; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; NLRP3; Pancreas; Pancreas - cytology; Pancreas - drug effects; Pancreas - immunology; Pharmacology & Pharmacy; Science & Technology; Sulfonylurea; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacology; ACTIVATION; EFFICACY; inflammasomes; MACROPHAGES; DRUG DISCOVERY; MECHANISMS; IDENTIFICATION; OBESITY; POLYPHARMACOLOGY; inflammation; RESISTANCE; NLRP3; multi-target; diabetes; TYPE-2 DIABETES-MELLITUS
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700270

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. Computer‐aided inhibitor design: Nonpeptidic inhibitors of the aspartic proteases plasmepsin II and IV were developed that bear a tetrahydro‐1H‐azepine scaffold. Structural modifications of the initial lead in a consecutive design cycle led to inhibitors with affinities in the nanomolar range. The Ki values are generally in good agreement with the design hypothesis, thus supporting the predicted binding mode for both plasmepsins.