Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer's disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16).

• Publication type
• Journal Article MeSH

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.

• Keywords
• 17β-hydroxysteroid dehydrogenase type 10, ABAD, Alzheimer’s disease, benzothiazole, inhibitor, neurodegeneration,
• 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
• Names of Substances
• 3-Hydroxyacyl CoA Dehydrogenases MeSH
• Benzothiazoles MeSH
• HSD17B10 protein, human MeSH Browser
• Enzyme Inhibitors MeSH
• Urea MeSH
• Recombinant Proteins 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.

• Keywords
• 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), amyloid binding alcohol dehydrogenase (ABAD), benzothiazole, Alzheimer’s disease (AD), amyloid-beta peptide (Aβ), mitochondria,
• 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
• Names of Substances
• 17-Hydroxysteroid Dehydrogenases MeSH
• Amyloid beta-Peptides MeSH
• Benzothiazoles MeSH
• Urea MeSH

Several neurodegenerative disorders including Alzheimer's disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease's progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.

• Keywords
• Alzheimer’s disease, amyloid-beta binding alcohol dehydrogenase (ABAD), benzothiazole, casein kinase 1 (CK1), neurodegeneration,
• MeSH
• 3-Hydroxyacyl CoA Dehydrogenases metabolism   MeSH
• Phenylurea Compounds chemistry   pharmacology   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Casein Kinase I antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Neurodegenerative Diseases drug therapy   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3-Hydroxyacyl CoA Dehydrogenases MeSH
• Phenylurea Compounds MeSH
• HSD17B10 protein, human MeSH Browser
• Enzyme Inhibitors MeSH
• Casein Kinase I MeSH