Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction.
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.
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.
Ahmed
A
Elkamhawy
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.
Jung-Eun
JE
Park
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.
Ahmed H E
AHE
Hassan
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.
Hyunhwa
H
Ra
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.
Ae Nim
AN
Pae
Department of Global Medical Science, Sungshin Women's University, Seoul 142-732, Republic of Korea.
Jiyoun
J
Lee
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.
Beoung-Geon
BG
Park
Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
Bongjin
B
Moon
Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
Hyun-Mee
HM
Park
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.
Eun Joo
EJ
Roh
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D055808:Drug Discovery; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C000616832:1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea; D016229:Amyloid beta-Peptides; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D010879:Piperazines; D016572:Cyclosporine; D014508:Urea
Alzheimer's disease (AD); Mitochondrial permeability transition pore (mPTP); Molecular docking; Pyridyl-urea; β-amyloid peptide (Aβ)