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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Laura AitkenFrank Gunn-Moore

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.

References

Sep 3, 2004·Journal of Molecular Biology·Charles R KissingerJ Ernest Villafranca
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jia YaoRoberta Diaz Brinton
Feb 24, 2010·The Biochemical Journal·Kirsty E A MuirheadFrank J Gunn-Moore
Jul 27, 2011·Biochemical Society Transactions·Eva BorgerFrank J Gunn-Moore
Feb 1, 2014·Current Alzheimer Research·Koteswara R ValaasaniShirley S Yan
Mar 19, 2016·Chembiochem : a European Journal of Chemical Biology·Laura AitkenFrank J Gunn-Moore

❮ Previous
Next ❯

Citations

Jan 1, 2020·Biomolecules·Gabriela Dumitrita StanciuDaniela Carmen Ababei
Dec 5, 2019·Current Topics in Medicinal Chemistry·Jiayang XieBing Niu
Feb 23, 2021·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Haizhou ZhuSwati S More

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
surface plasmon resonance
Assay
column chromatography

Software Mentioned

GraphPad Prism
Xcalibur

Related Concepts

Related Feeds

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.