Inflammation Control: Novel Inhibitors of IL-1β Release

• Main Author: Hammadi, Halah Hamid
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2019
• Subjects: Adenosine triphosphate; Aging; Alzheimers disease; Amino acids; Apoptosis; Binding sites; Biological assays; Boron; Cellular biology; Chloride; Chlorine; Enzymes; Inflammation; Neurosciences; Pharmaceutical sciences; Phosphorylation
• ISBN: 9798358419094

The NLRP3 inflammasome is a multiprotein signaling platform that controls the inflammatory response. It is assembled following the detection of pathogenic microorganisms, and it activates the production of caspase-1 to produce IL-1β cytokine and to induce pyroptotic cell death. The importance of the NLRP3 inflammasome reaches beyond its role in host defense against infectious agents, as the deregulated NLRP3 inflammasome is associated with the development of cancer, neurodegenerative (for example Alzheimer's disease (AD)) and metabolic diseases. The NLRP3 inflammasome is recognized as a therapeutic target for the treatment of sterile inflammation.Medicinal chemistry was used to design and synthesise four novel boron compounds (NBC series) based on the potent NLRP3 inflammasome oxazaborine inhibitors BC23 and NBC6. The synthesis of the 2,2-diphenyl-1,3,2-diazaborine inhibitors involved the borylation of β-enaminone intermediates using diphenyborinic anhydride. Here the syntheses of analogues of NBC6 were achieved by the replacement of the 5-acetyl-group by 5-cyano (NBC18) and by 5-amide (NBC24). BC23 was modified by replacing the 4-CCl3 group with 4-phenyl (NBC23) and 4-EtS (NBC26). NBC compounds were tested for IL-1β inhibitory activity in an NLRP3-induced human THP-1 cell line. Structure-activity relationship analysis revealed that a boron atom chelated in an oxazaborine ring, together with the presence of a 4-CCl3 group was favoured for IL-1β inhibitory activity.Brough and co-workers reported that the Volume-Regulated Anion Channel (VRAC) is a regulator of the NLRP3 inflammasome and a potential drug target for inflammatory disorders. Flufenamic acid treatment in a mouse model with AD abated neurotoxic inflammation in the brain and reversed memory loss. Medicinal chemistry was utilized to design and synthesise 46 compounds (Novel Volume-Regulated (NVR) series) based on the lead flufenamic acid. The structural features that were modified included the carboxylic acid, the length and type of linker between the aromatic rings, and the substituents on both phenyl rings. The most active compounds identified, with an IC50 of ~1 µM for the inhibition of IL-1β release in BMDM and iBMDM cells, contained a tetrazole acidic group, a urea linker, and fluoro, chloro and/or trifluoromethyl substituents on the aromatic rings.