Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.

• MeSH
• 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors   chemistry   MeSH
• Enzyme Activation MeSH
• Alzheimer Disease drug therapy   MeSH
• Benzothiazoles chemistry   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Kinetics MeSH
• Humans MeSH
• Urea chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Recombinant Proteins MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

: 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.

• MeSH
• 17-Hydroxysteroid Dehydrogenases antagonists & inhibitors   chemistry   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Benzothiazoles chemistry   MeSH
• Cell Line MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Urea chemistry   MeSH
• Molecular Structure MeSH
• Drug Design MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH