Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: An fast and atom efficient access to 1-aryl-3-benzylureas

Fabio Lo Monte, Thomas Kramer, Alexander Boländer, Batya Plotkin, Hagit Eldar-Finkelman, Ana Fuertes, Juan Dominguez, Boris Schmidt

Research output: Contribution to journalArticlepeer-review

Abstract

The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC 50 = 140 nM) and the pyridylurea 62 (IC 50 = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC 50 = 330 nM) in our assays.

Original languageEnglish
Pages (from-to)5610-5615
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number18
DOIs
StatePublished - 15 Sep 2011

Keywords

  • Alzheimer disease
  • Glycogen synthase kinase 3 (GSK-3)
  • Microwave irradiation
  • Structure-activity relationship (SAR)
  • Suzuki coupling

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