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
  • 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: [email protected].
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).