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Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy.
Bioorg Med Chem. 2018 01 01; 26(1):232-244.BM

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.

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Authors+Show Affiliations

Yeon SK
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.
Choi JW
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.
Park JH
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Lee YR
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.
Kim HJ
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.
Shin SJ
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.
Jang BK
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Kim S
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.
Bahn YS
Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
Han G
Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
Lee YS
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
Pae AN
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.
Park KD
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.

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAnimalsBenzene DerivativesDisease Models, AnimalDose-Response Relationship, DrugHumansMaleMiceMice, Inbred C57BLMolecular StructureMonoamine OxidaseMonoamine Oxidase InhibitorsParkinson DiseaseStructure-Activity Relationship

Pub Type(s)

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

Language

eng

PubMed ID

29198609

Citation

Yeon, Seul Ki, et al. "Synthesis and Evaluation of Biaryl Derivatives for Structural Characterization of Selective Monoamine Oxidase B Inhibitors Toward Parkinson's Disease Therapy." Bioorganic & Medicinal Chemistry, vol. 26, no. 1, 2018, pp. 232-244.
Yeon SK, Choi JW, Park JH, et al. Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy. Bioorg Med Chem. 2018;26(1):232-244.
Yeon, S. K., Choi, J. W., Park, J. H., Lee, Y. R., Kim, H. J., Shin, S. J., Jang, B. K., Kim, S., Bahn, Y. S., Han, G., Lee, Y. S., Pae, A. N., & Park, K. D. (2018). Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy. Bioorganic & Medicinal Chemistry, 26(1), 232-244. https://doi.org/10.1016/j.bmc.2017.11.036
Yeon SK, et al. Synthesis and Evaluation of Biaryl Derivatives for Structural Characterization of Selective Monoamine Oxidase B Inhibitors Toward Parkinson's Disease Therapy. Bioorg Med Chem. 2018 01 1;26(1):232-244. PubMed PMID: 29198609.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy. AU - Yeon,Seul Ki, AU - Choi,Ji Won, AU - Park,Jong-Hyun, AU - Lee,Ye Rim, AU - Kim,Hyeon Jeong, AU - Shin,Su Jeong, AU - Jang,Bo Ko, AU - Kim,Siwon, AU - Bahn,Yong-Sun, AU - Han,Gyoonhee, AU - Lee,Yong Sup, AU - Pae,Ae Nim, AU - Park,Ki Duk, Y1 - 2017/11/24/ PY - 2017/10/30/received PY - 2017/11/22/revised PY - 2017/11/23/accepted PY - 2017/12/5/pubmed PY - 2018/1/6/medline PY - 2017/12/5/entrez KW - Benzyloxyphenyl derivatives KW - MAO-B inhibitor KW - MPTP mouse model KW - Parkinson’s disease SP - 232 EP - 244 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 26 IS - 1 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/29198609/Synthesis_and_evaluation_of_biaryl_derivatives_for_structural_characterization_of_selective_monoamine_oxidase_B_inhibitors_toward_Parkinson's_disease_therapy_ DB - PRIME DP - Unbound Medicine ER -