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

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.
Seul Ki Yeon 1,  Ji Won Choi 1,  Jong-Hyun Park 2,  Ye Rim Lee 3,  Hyeon Jeong Kim 1,  Su Jeong Shin 1,  Bo Ko Jang 2,  Siwon Kim 4,  Yong-Sun Bahn 5,  Gyoonhee Han 5,  Yong Sup Lee 6,  Ae Nim Pae 7,  Ki Duk Park 8
Affiliations

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: [email protected].
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.

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