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.
['Elkamhawy|Ahmed|A|', 'Park|Jung-Eun|JE|', 'Hassan|Ahmed H E|AHE|', 'Ra|Hyunhwa|H|', 'Pae|Ae Nim|AN|', 'Lee|Jiyoun|J|', 'Park|Beoung-Geon|BG|', 'Moon|Bongjin|B|', 'Park|Hyun-Mee|HM|', 'Roh|Eun Joo|EJ|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D002470:Cell Survival D002478:Cells, Cultured D016572:Cyclosporine D055808:Drug Discovery D006624:Hippocampus D007166:Immunosuppressive Agents D053078:Membrane Potential, Mitochondrial D051379:Mice D008928:Mitochondria D033681:Mitochondrial Membrane Transport Proteins D062105:Molecular Docking Simulation D009474:Neurons D010879:Piperazines D011487:Protein Conformation D014508:Urea
Pyridyl-urea Mitochondrial permeability transition pore (mPTP) Molecular docking Alzheimer's disease (AD) β-amyloid peptide (Aβ)