Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment

详细信息    查看全文

• 作者：Lukas Hroch^a ; ^b ; ^&dagger ; ; Ondrej Benek^b ; ^c ; ^&dagger ; ; Patrick Guest^d ; ^&dagger ; ; Laura Aitken^d ; ^&dagger ; ; Ondrej Soukup^b ; Jana Janockova^b ; Karel Musil^b ; ^f ; Vlastimil Dohnal^f ; Rafael Dolezal^b ; ^e ; Kamil Kuca^b ; ^f ; Terry K Smith^g ; Frank Gunn-Moore^d ; Kamil Musilek^b ; ^f ; ^{kamil.musilek@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alzheimer&rsquo ; s disease (AD) ; Amyloid-beta peptide (Aβ) ; Mitochondria ; Amyloid binding alcohol dehydrogenase (ABAD) ; 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) ; Benzothiazole ; Riluzole
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 August 2016
• 年：2016
• 卷：26
• 期：15
• 页码：3675-3678
• 全文大小：474 K

文摘

Amyloid-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.