Novel Benzothiazole-based Ureas As 17β-HSD10 Inhibitors, A Potential Alzheimer's Disease Treatment

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Aug 1

PMID 31362457

Citations 12

Authors

Laura Aitken

Ondrej Benek

Brogan E McKelvie

Rebecca E Hughes

Lukas Hroch

Monika Schmidt

Louise L Major

Lucie Vinklarova

Kamil Kuca

Terry K Smith

Kamil Musilek

Frank J Gunn-Moore

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Synthesis and biological characterization of a 17β hydroxysteroid dehydrogenase type 10 (17β-HSD10) inhibitor.

Dow L, Pathirage R, Erickson H, Amani E, Ronning D, Trippier P RSC Med Chem. 2024; .

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The therapeutic value of thiazole and thiazolidine derivatives in Alzheimer's disease: a systematic literature review.

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

Hanzlova M, Slavikova B, Morozovova M, Musilek K, Rotterova A, Zemanova L ACS Omega. 2024; 9(10):12116-12124.

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

Hanzlova M, Miskerikova M, Rotterova A, Chalupova K, Jurkova K, Hamsikova M ACS Med Chem Lett. 2023; 14(12):1724-1732.

PMID: 38116418 PMC: 10726454. DOI: 10.1021/acsmedchemlett.3c00355.

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