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

TaeHun Kim; Ha Yun Yang; Beoung Gun Park; Seo Yun Jung; Jong-Hyun Park; Ki Duk Park; Sun-Joon Min; Jinsung Tae; Hyejin Yang; Suengmok Cho; Sung Jin Cho; Hyundong Song; Inhee Mook-Jung; Jiyoun Lee; Ae Nim Pae

doi:10.1016/j.ejmech.2016.11.017

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

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

Authors

TaeHun Kim¹, Ha Yun Yang², Beoung Gun Park³, Seo Yun Jung³, Jong-Hyun Park³, Ki Duk Park¹, Sun-Joon Min⁴, Jinsung Tae⁵, Hyejin Yang⁶, Suengmok Cho⁶, Sung Jin Cho⁷, Hyundong Song⁸, Inhee Mook-Jung⁸, Jiyoun Lee⁹, Ae Nim Pae¹⁰

Affiliations

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.

PMID: 27855359
DOI: 10.1016/j.ejmech.2016.11.017

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.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism
Animals
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology
Benzimidazoles / therapeutic use*
Cognition / drug effects
Humans
Ligands
Male
Membrane Potential, Mitochondrial / drug effects
Memory / drug effects
Mice, Transgenic
Mitochondria / drug effects*
Mitochondria / metabolism
Mitochondria / pathology
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Permeability Transition Pore
Models, Molecular
Rats, Sprague-Dawley
Receptors, GABA / metabolism

Substances

Amyloid beta-Peptides
Benzimidazoles
Ligands
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Receptors, GABA
TSPO protein, human