: 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.

Biomedical Science Research Complex University of St Andrews North Haugh St Andrews KY16 9ST UK

Cancer Research UK Edinburgh Centre MRC Institute of Genetics and Molecular Medicine Western General Hospital University of Edinburgh Edinburgh EH4 2XU UK

University Hospital Biomedical Research Center Sokolska 581 500 05 Hradec Kralove Czech Republic

University of Hradec Kralove Faculty of Science Department of Chemistry Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

University of St Andrews School of Biology Medical and Biological Sciences Building North Haugh St Andrews KY16 9TF UK

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C-3 Steroidal Hemiesters as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 10

Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity

Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer's Disease Treatment