Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy

Seul Ki Yeon; Ji Won Choi; Jong-Hyun Park; Ye Rim Lee; Hyeon Jeong Kim; Su Jeong Shin; Bo Ko Jang; Siwon Kim; Yong-Sun Bahn; Gyoonhee Han; Yong Sup Lee; Ae Nim Pae; Ki Duk Park

doi:10.1016/j.bmc.2017.11.036

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy

Bioorg Med Chem. 2018 Jan 1;26(1):232-244. doi: 10.1016/j.bmc.2017.11.036. Epub 2017 Nov 24.

Authors

Seul Ki Yeon¹, Ji Won Choi¹, Jong-Hyun Park², Ye Rim Lee³, Hyeon Jeong Kim¹, Su Jeong Shin¹, Bo Ko Jang², Siwon Kim⁴, Yong-Sun Bahn⁵, Gyoonhee Han⁵, Yong Sup Lee⁶, Ae Nim Pae⁷, Ki Duk Park⁸

Affiliations

¹ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
² Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea.
³ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
⁴ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea.
⁵ Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
⁶ KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
⁷ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea.
⁸ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. Electronic address: kdpark@kist.re.kr.

PMID: 29198609
DOI: 10.1016/j.bmc.2017.11.036

Abstract

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC₅₀: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.

Keywords: Benzyloxyphenyl derivatives; MAO-B inhibitor; MPTP mouse model; Parkinson’s disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / administration & dosage
Animals
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Parkinson Disease / drug therapy*
Parkinson Disease / metabolism
Parkinson Disease / pathology
Structure-Activity Relationship

Substances

Benzene Derivatives
Monoamine Oxidase Inhibitors
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Monoamine Oxidase
monoamine oxidase A, human