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Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction

조회수 : 104 등록일 : 2017.04.21 00:00

저자 : Moon, B (Moon, Bongjin)
출처 : EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
출판일 : 2017.03.10
 
 
Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction
 
 
Elkamhawy, A (Elkamhawy, Ahmed)[ 1,2 ] ; Park, JE (Park, Jung-Eun)[ 1,3 ] ; Hassan, AHE (Hassan, Ahmed H. E.)[ 4,5 ] ; Ra, H (Ra, Hyunhwa)[ 1,3 ] ; Pae, AN (Pae, Ae Nim)[ 6,7 ] ; Lee, J (Lee, Jiyoun)[ 8 ] ; Park, BG (Park, Beoung-Geon)[ 6,9 ] ; Moon, B (Moon, Bongjin)[ 3 ] ; Park, HM (Park, Hyun-Mee)[ 10 ] ; Roh, EJ (Roh, Eun Joo)[ 1,7 ]
 
 
[ 1 ] KIST, Chem Kinom Res Ctr, Seoul 02792, South Korea
[ 2 ] Mansoura Univ, Fac Pharm, Dept Organ Pharmaceut Chem, Mansoura 35516, Egypt
[ 3 ] Sogang Univ, Dept Chem, Seoul 04107, South Korea
[ 4 ] Mansoura Univ, Fac Pharm, Dept Med Chem, Mansoura 35516, Egypt
[ 5 ] Kyung Hee Univ, Coll Pharm, Dept Pharm, Med Chem Lab, Seoul 02447, South Korea
[ 6 ] KIST, Convergence Res Ctr Diag Treatment & Care Syst De, Seoul 02792, South Korea
[ 7 ] Korea Univ Sci & Technol UST, Dept Biol Chem, Daejeon 305350, South Korea
[ 8 ] Sungshin Womens Univ, Dept Global Med Sci, Seoul 142732, South Korea
[ 9 ] Korea Univ, Sch Life Sci & Biotechnol, Seoul 02792, South Korea
[ 10 ] Korea Inst Sci & Technol, Adv Anal Ctr, Seoul 02792, South Korea
 
 
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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