Structure–activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

doi:10.1016/j.bmcl.2011.08.009

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 19, 1 October 2011, Pages 5774-5777

https://doi.org/10.1016/j.bmcl.2011.08.009 Get rights and content

Abstract

Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure–activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 μM after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5–3.9-fold after 24 h with an EC₅₀ of 0.5 μM.

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Acknowledgment

We are grateful to the National Institutes of Health (U24 NS04933901 and R01 NS064275), the Harvard NeuroDiscovery Center, ALS Therapy Alliance, Inc and Project ALS for financial support.

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Citation Excerpt :
A new class of molecules, the thiopyridazines, was identified from high-throughput screening of a library of approximately 140,000 compounds [233]. A hit-to-lead effort was undertaken, resulting in an enhancement of SLC1A2 levels by more than six fold at a compound concentration of less than 5 μM [234]. More recently, Chelini et al. [235] synthesized and characterized additional novel neuroprotective pyridazine derivatives that act as activators of SLC1A2/GLT1 and tested them in an animal model of neuropathic pain induced by oxaliplatin.
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Structure–activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

Abstract

Graphical abstract

Section snippets

Acknowledgment

Neurochem. Int.

J. Biol. Chem.

Neurochem. Int.

Brain. Res. Rev.

J. Biomol. Screen.

Hum. Mol. Genet.