期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 128, 期 -, 页码 56-69出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.12.057
关键词
Mitochondrial permeability transition pore (mPTP); Alzheimer's disease (AD); beta-amyloid peptide (A beta); Pyridyl-urea; Molecular docking
资金
- Korea Institute of Science and Technology [2E26090]
- Creative Fusion Research Program through the Creative Allied Project National Research Council of Science Technology [CAP-12-1-KIST]
- Ministry of Science, ICT & Future Planning, Republic of Korea [2E26090] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Herein, we report a new series of aliphatic substituted pyridyl-urea small molecules synthesized as potential modulators for amyloid beta (A beta) induced mitochondrial dysfunction. Their blocking activities against A beta-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (Delta Psi m). The inhibitory activity of sixteen compounds against A beta-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. (C) 2016 Published by Elsevier Masson SAS.
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