Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer’s disease treatment

Funding: This work was supported by Alzheimer’s Society (specifically The Barcopel Foundation), Scottish Universities Life Science Alliance (SULSA), The Rosetrees Trust, WT-ISSF and RS MacDonald Charitable Trust, Ministry of Education, Youth and Sports of Czech Republic (project ESF no. CZ.02.1.01/0.0/0.0/18_069/0010054), and University of Hradec Kralove (Faculty of Science, no. VT2019-2021, SV2115-2018, and Postdoctoral job positions at UHK).It has long been established, that mitochondrial dysfunction in Alzheimer’s disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.Publisher PDFPeer reviewe

Data underpinning: Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer’s disease treatment

All raw data (enzyme assays, enzyme kinetics, thermal shift, IC50 calculations) underpinning: Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer’s disease treatment. The data files are not yet publicly available. Enquiries and requests for data should be directed to the publication's corresponding authors: Aitken, L., Benek, O., McKelvie, B., Hughes, R. E., Hroch, L., Schmidt, M., Major, L. L., Vinklarova, L., Kuca, K., Smith, T. K., Musilek, K. & Gunn-Moore, F. J., 29 Jul 2019, In : Molecules. 24, 15, 2757