IN VITRO EVALUATION OF BENZOTHIAZOLE-BASED UREAS AS POTENTIAL ABAD/17β-HSD10 MODULATORS FOR ALZHEIMER'S DISEASE THERAPEUTICS

Abstract

The mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), has been shown to mediate the cytotoxic effects of Amyloid-β within the Alzheimer's diseased brain. Mutational studies have shown that ABAD must be catalytically active for cytotoxicity to be observed and therefore the direct inhibition of ABAD may offer a novel therapeutic strategy to treat the disease. In 2006, Xie et al.1 identified benzothiazole urea analogues capable of perturbing the ABAD- Aβ interaction. We hypothesised that the capability of these analogues to disrupt the interaction may infer the ability to bind to ABAD, which in turn may inhibit ABAD activity. Consequently we have generated many series of benzothiazole urea derivatives and assessed their ability to inhibit ABAD; identifying and characterising several potent inhibitors and we have now made several bioisostere modifications to these molecules2,3,4. To assess the compounds therapeutic potential we are using many different techniques, but our primary screening strategy utilises recombinant ABAD enzyme extract to measure ABAD activity, followed by cell based and biophysical de-selection assays to verify the inhibitory nature, the cell permeability and cytotoxicity of these compounds. Medicinal chemistry is utilised to optimise the molecules pharmacokinetic properties and potency, whilst in sillico physiochemical prediction software and molecular modelling aim to optimise the chemical space available. We have characterised several different types of benzothiazole molecules at the recombinant protein level2,3,4 and now at the cellular level. These molecules exhibit nM potency in the protein assay and low μM potency in the cellular assays. These molecules exhibit promise as ABAD inhibitors and with further modifications and in vivo screening these compounds have the potential to be used as therapeutics in AD.