2. Academic Validation
  3. Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction

Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction

  • Eur J Med Chem. 2017 Mar 10:128:56-69. doi: 10.1016/j.ejmech.2016.12.057.
Ahmed Elkamhawy 1,  Jung-Eun Park 2,  Ahmed H E Hassan 3,  Hyunhwa Ra 2,  Ae Nim Pae 4,  Jiyoun Lee 5,  Beoung-Geon Park 6,  Bongjin Moon 7,  Hyun-Mee Park 8,  Eun Joo Roh 9
Affiliations

Affiliations

  • 1 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 4 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, Republic of Korea.
  • 5 Department of Global Medical Science, Sungshin Women's University, Seoul 142-732, Republic of Korea.
  • 6 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul 02792, Republic of Korea.
  • 7 Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
  • 8 Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 9 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, Republic of Korea. Electronic address: r8636@kist.re.kr.
PMID: 28152427 DOI: 10.1016/j.ejmech.2016.12.057
Abstract

Herein, we report a new series of aliphatic substituted pyridyl-urea small molecules synthesized as potential modulators for amyloid beta (Aβ) induced mitochondrial dysfunction. Their blocking activities against Aβ-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The inhibitory activity of sixteen compounds against Aβ-induced mPTP opening was superior or almost similar to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea (5x) effectively maintained mitochondrial function and cell viabilities on ATP assay, MTT assay, and ROS assay. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for 5x with Cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, hERG and BBB-PAMPA assays presented safe cardiotoxicity and high CNS bioavailability profiles for 5x. Taken as a whole, this report presents compound 5x as a new nonpeptidyl mPTP blocker may hold a promise for further development of Alzheimer's disease (AD) therapeutics.

Keywords

Alzheimer's disease (AD); Mitochondrial permeability transition pore (mPTP); Molecular docking; Pyridyl-urea; β-amyloid peptide (Aβ).

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