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Eur J Med Chem. 2017 Jan 5;125:1172-1192. doi: 10.1016/j.ejmech.2016.11.017. Epub 2016 Nov 9.

Discovery of benzimidazole derivatives as modulators of mitochondrial function: A potential treatment for Alzheimer's disease.

Author information

1
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejon 305-350, Republic of Korea.
2
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
3
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
4
Department of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do 15888, Republic of Korea.
5
Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
6
Korea Food Research Institute, Sungnam 463-746, Republic of Korea.
7
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
8
Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Seoul 110-799, Jongno-gu, Republic of Korea.
9
Department of Global Medical Science, Sungshin University, Seoul 142-732, Republic of Korea. Electronic address: jlee@sungshin.ac.kr.
10
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejon 305-350, Republic of Korea. Electronic address: anpae@kist.re.kr.

Abstract

In this study, we designed a library of compounds based on the structures of well-known ligands of the 18 kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aβ-induced toxicity in vitro and in vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent in vitro and in vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD.

KEYWORDS:

Alzheimer's disease; Aβ; Mitochondrial dysfunction; Mitochondrial permeability transition pore; TSPO; Translocator protein

PMID:
27855359
DOI:
10.1016/j.ejmech.2016.11.017
[Indexed for MEDLINE]

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