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

Laura Aitken; Ondrej Benek; Brogan McKelvie; Rebecca E. Hughes; Lukas Hroch; Monika Schmidt; Louise L Major; Lucie Vinklarova; Kamil Kuca; Terry K Smith; Kamil Musilek; Frank J Gunn-Moore

doi:10.3390/molecules24152757

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

Laura Aitken, Ondrej Benek, Brogan McKelvie, Rebecca E. Hughes, Lukas Hroch, Monika Schmidt, Louise L Major, Lucie Vinklarova, Kamil Kuca, Terry K Smith, Kamil Musilek, Frank J Gunn-Moore

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	2757
Journal	Molecules
Volume	24
Issue number	15
DOIs	https://doi.org/10.3390/molecules24152757
Publication status	Published - 29 Jul 2019

Keywords

Alzheimer's disease (AD)
Amyloid-beta peptide (Aβ)
Mitochondria
Amyloid binding alcohol dehydrogenase (ABAD)
17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10)
Benzothiazole

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Aitken_2019_Mol_NovelBenzothiazole-basedUreas_CCBY-VoR
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 968 KBLicence: CC BY

Institutional Strategic Support Fund: Insitutional Stratigic Support Fund (ISSF)
Naismith, J. (PI)
The Wellcome Trust
1/03/12 → 28/02/15
Project: Standard

Data underpinning: Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer’s disease treatment
Aitken, L. (Creator), Benek, O. (Contributor), McKelvie, B. (Contributor), Hughes, R. (Contributor), Hroch, L. (Contributor), Major, L. L. (Creator), kuca, K. (Contributor), Smith, T. K. (Supervisor), Musilek, K. (Contributor) & Gunn-Moore, F. J. (Supervisor), University of St Andrews, 2018
DOI: 10.17630/a9bb5ff9-b6cf-4175-9840-961d4c47651a
Dataset

Cite this

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title = "Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer{\textquoteright}s disease treatment",

abstract = "It has long been established, that mitochondrial dysfunction in Alzheimer{\textquoteright}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 = "Alzheimer's disease (AD), Amyloid-beta peptide (Aβ), Mitochondria, Amyloid binding alcohol dehydrogenase (ABAD), 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10), Benzothiazole",

author = "Laura Aitken and Ondrej Benek and Brogan McKelvie and Hughes, {Rebecca E.} and Lukas Hroch and Monika Schmidt and Major, {Louise L} and Lucie Vinklarova and Kamil Kuca and Smith, {Terry K} and Kamil Musilek and Gunn-Moore, {Frank J}",

note = "Funding: This work was supported by Alzheimer{\textquoteright}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). ",

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doi = "10.3390/molecules24152757",

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T1 - Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential Alzheimer’s disease treatment

AU - Aitken, Laura

AU - Benek, Ondrej

AU - McKelvie, Brogan

AU - Hughes, Rebecca E.

AU - Hroch, Lukas

AU - Schmidt, Monika

AU - Major, Louise L

AU - Vinklarova, Lucie

AU - Kuca, Kamil

AU - Smith, Terry K

AU - Musilek, Kamil

AU - Gunn-Moore, Frank J

N1 - 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).

PY - 2019/7/29

Y1 - 2019/7/29

N2 - 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.

AB - 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.

KW - Alzheimer's disease (AD)

KW - Amyloid-beta peptide (Aβ)

KW - Mitochondria

KW - Amyloid binding alcohol dehydrogenase (ABAD)

KW - 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10)

KW - Benzothiazole

U2 - 10.3390/molecules24152757

DO - 10.3390/molecules24152757

M3 - Article

SN - 1420-3049

VL - 24

JO - Molecules

JF - Molecules

IS - 15

M1 - 2757

ER -

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

Abstract

Keywords

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Projects

Institutional Strategic Support Fund: Insitutional Stratigic Support Fund (ISSF)

Datasets

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

Cite this