671212-34-3Relevant articles and documents
Inhibition of Ebola virus infection: Identification of niemann-pick C1 as the target by optimization of a chemical probe
Lee, Kyungae,Ren, Tao,Co?té, Marceline,Gholamreza, Berahman,Misasi, John,Bruchez, Anna,Cunningham, James
supporting information, p. 239 - 243 (2013/03/28)
A high-throughput screen identified adamantane dipeptide 1 as an inhibitor of Ebola virus (EboV) infection. Hit-to-lead optimization to determine the structure-activity relationship (SAR) identified the more potent EboV inhibitor 2 and a photoaffinity labeling agent 3. These antiviral compounds were employed to identify the target as Niemann-Pick C1 (NPC1), a host protein that binds the EboV glycoprotein and is essential for infection. These studies establish NPC1 as a promising target for antiviral therapy.
1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases
Koch, Pierre,Akkari, Rhalid,Brunschweiger, Andreas,Borrmann, Thomas,Schlenk, Miriam,Küppers, Petra,K?se, Meryem,Radjainia, Hamid,Hockemeyer, J?rg,Drabczyńska, Anna,Kie?-Kononowicz, Katarzyna,Müller, Christa E.
, p. 7435 - 7452 (2013/11/19)
Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f] purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl- 6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC50 human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A1/A2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H) dione (19f, Ki, human receptors, A1: 0.249 μM, A 2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9- tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, Ki A 1: 0.605 μM, Ki A2A: 0.417 μM, IC 50 MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo.
Structure-activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs
Scapecchi, Serena,Martini, Elisabetta,Manetti, Dina,Ghelardini, Carla,Martelli, Cecilia,Dei, Silvia,Galeotti, Nicoletta,Guandalini, Luca,Romanelli, Maria Novella,Teodori, Elisabetta
, p. 71 - 85 (2007/10/03)
Structure-activity relationships on two novel potent cognition enhancing drugs, unifiram (DM232, 1) and sunifiram (DM235, 2), are reported. Although none of the compounds synthesised reached the potency of the parent drugs, some fairly active compounds have been identified that may represent new leads to develop other cognition enhancing drugs. An interesting result of this research is the identification of two compounds (13 and 14) that are endowed with amnesing activity (the opposite of the activity of the original molecules) and are nearly equipotent to scopolamine. Moreover, two compounds of the series (5 and 6) were found endowed with analgesic activity on a rat model of neuropathic pain at the dose of 1 mg/kg.
