Elkamhawy, Ahmed Park, Jung-Eun Hassan, Ahmed H. E. Ra, Hyunhwa Pae, Ae Nim Lee, Jiyoun Park, Beoung-Geon Moon, Bongjin Park, Hyun-Mee Roh, Eun Joo 2024-01-20T02:01:36Z 2024-01-20T02:01:36Z 2021-09-01 2017-03-10 0223-5234 https://pubs.kist.re.kr/handle/201004/122952 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. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PERMEABILITY TRANSITION CYCLOPHILIN-D CELL-DEATH INHIBITORS INVOLVEMENT CHEMISTRY DISEASE Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction Article 10.1016/j.ejmech.2016.12.057 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.128, pp.56 - 69 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 128 56 69 scie scopus 000397180600006 2-s2.0-85010739249 Chemistry, Medicinal Pharmacology & Pharmacy Article PERMEABILITY TRANSITION CYCLOPHILIN-D CELL-DEATH INHIBITORS INVOLVEMENT CHEMISTRY DISEASE Mitochondrial permeability transition pore (mPTP) Alzheimer&apos s disease (AD) beta-amyloid peptide (A beta) Pyridyl-urea Molecular docking