Show simple item record

Files in this item

Thumbnail

Item metadata

dc.contributor.authorHroch, Lukas
dc.contributor.authorBenek, Ondrej
dc.contributor.authorGuest, Patrick
dc.contributor.authorAitken, Laura
dc.contributor.authorSoukup, Ondrej
dc.contributor.authorJanockova, Jana
dc.contributor.authorMusil, Karel
dc.contributor.authorDohnal, Vlastimil
dc.contributor.authorDolezal, Rafael
dc.contributor.authorKuca, Kamil
dc.contributor.authorSmith, Terry K
dc.contributor.authorGunn-Moore, Frank J
dc.contributor.authorMusilek, K
dc.date.accessioned2017-08-15T08:44:02Z
dc.date.available2017-08-15T08:44:02Z
dc.date.issued2016-08-01
dc.identifier.citationHroch , L , Benek , O , Guest , P , Aitken , L , Soukup , O , Janockova , J , Musil , K , Dohnal , V , Dolezal , R , Kuca , K , Smith , T K , Gunn-Moore , F J & Musilek , K 2016 , ' Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment ' , Bioorganic and Medicinal Chemistry Letters , vol. 26 , no. 15 , pp. 3675-3678 . https://doi.org/10.1016/j.bmcl.2016.05.087en
dc.identifier.issn0960-894X
dc.identifier.otherPURE: 243084363
dc.identifier.otherPURE UUID: 13411b13-1dd3-495c-8f6f-8b0f59d234fd
dc.identifier.otherScopus: 84973563591
dc.identifier.otherORCID: /0000-0003-3422-3387/work/34730414
dc.identifier.otherORCID: /0000-0001-7259-4491/work/31318395
dc.identifier.otherWOS: 000380574100058
dc.identifier.urihttp://hdl.handle.net/10023/11451
dc.descriptionThis work was supported by the Ministry of Health of the Czech Republic (no. NV15-28967A), Charles University in Prague (no. GAUK B-CH/992214, SVV 260 291) and the Alzheimer’s Society (specifically The Barcopel Foundation). This research is part-funded by the MSD Scottish Life Sciences fund.en
dc.description.abstractAmyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer’s disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds ( 37 , 39 ) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.
dc.format.extent4
dc.language.isoeng
dc.relation.ispartofBioorganic and Medicinal Chemistry Lettersen
dc.rights© 2016 Elsevier Ltd. All rights reserved. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1016/j.bmcl.2016.05.087en
dc.subjectAlzheimer's disease (AD)en
dc.subjectAmyloid-beta peptide (Aβ)en
dc.subjectMitochondriaen
dc.subjectAmyloid binding alcohol dehydrogenase (ABAD)en
dc.subject17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10)en
dc.subjectBenzothiazoleen
dc.subjectRiluzoleen
dc.subjectR Medicine (General)en
dc.subjectQR Microbiologyen
dc.subjectNDASen
dc.subject.lccR1en
dc.subject.lccQRen
dc.titleDesign, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatmenten
dc.typeJournal itemen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.East of Scotland Bioscience Doctoral Training Partnershipen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.Institute of Behavioural and Neural Sciencesen
dc.identifier.doihttps://doi.org/10.1016/j.bmcl.2016.05.087
dc.description.statusPeer revieweden
dc.date.embargoedUntil2017-05-30


This item appears in the following Collection(s)

Show simple item record