Objective

Alzheimer’s disease (AD) is the most common form of dementia, associated with progressive cognitive impairment. Chronic deposition of amyloid&hypen;β in the brain stimulates persistent activation of the NLRP3 inflammasome, mediating a harmful inflammatory response through secretion of IL-1β. Heneka et al.1 showed that the activation of NLRP3 plays a key role in the progression of AD, suggesting that inhibition of NLRP3 and release of IL-1β may have a beneficial effect on patients with AD. Daniels et al.2 have recently shown that the fenamate class of non-steroidal anti-inflammatory drugs are effective and selective inhibitors of the NLRP3 inflammaome through their inhibition of volume regulated anion channel (VRAC) in macrophages. In an AD mouse model flufenamic acid inhibited NLRP3 via blockade of VRAC in the plasma membrane, inhibiting cognitive impairment and preventing memory loss. The aim of this project is to validate VRAC as a new therapeutic target for the treatment of AD. Forty fenamate analogues with a range of substituents on the aromatic rings, various chain lengths between the aromatic rings, and replacement of the carboxylic acid with a tetrazole ring, were synthesised and fully characterised by NMR spectroscopy and mass spectrometry.