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1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases.

Abstract
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, IC(50) 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, A2A: 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 A1: 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.
AuthorsPierre Koch, Rhalid Akkari, Andreas Brunschweiger, Thomas Borrmann, Miriam Schlenk, Petra Küppers, Meryem Köse, Hamid Radjainia, Jörg Hockemeyer, Anna Drabczyńska, Katarzyna Kieć-Kononowicz, Christa E Müller
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 23 Pg. 7435-52 (Dec 01 2013) ISSN: 1464-3391 [Electronic] England
PMID24139167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Monoamine Oxidase Inhibitors
  • Purinergic P1 Receptor Antagonists
  • Purines
  • Xanthines
  • Caffeine
  • Monoamine Oxidase
  • purine
Topics
  • Adenosine A1 Receptor Antagonists (chemistry, pharmacology)
  • Adenosine A2 Receptor Antagonists (chemistry, pharmacology)
  • Animals
  • CHO Cells
  • Caffeine (chemistry, pharmacology)
  • Cricetulus
  • Humans
  • Monoamine Oxidase (metabolism)
  • Monoamine Oxidase Inhibitors (chemistry, pharmacology)
  • Neurodegenerative Diseases (drug therapy, enzymology)
  • Purinergic P1 Receptor Antagonists (chemistry, pharmacology)
  • Purines (chemistry, pharmacology)
  • Xanthines (chemistry, pharmacology)

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