Journal of Enzyme Inhibition and Medicinal Chemistry (Jan 2019)

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3

  • M. Lourdes Sciú,
  • Victor Sebastián-Pérez,
  • Loreto Martinez-Gonzalez,
  • Rocio Benitez,
  • Daniel I. Perez,
  • Concepción Pérez,
  • Nuria E. Campillo,
  • Ana Martinez,
  • E. Laura Moyano

DOI
https://doi.org/10.1080/14756366.2018.1530223
Journal volume & issue
Vol. 34, no. 1
pp. 87 – 96

Abstract

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Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer’s disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1–3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood–brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.

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