A novel series of positive modulators of the AMPA receptor: Discovery and structure based hit-to-lead studies

Starting from an HTS hit, the evolution of lead compound 22, a positive allosteric modulator of the AMPA receptor is described using structure based drug design. Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor mod...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (19), p.5753-5756
Main Authors: Jamieson, Craig, Basten, Stephanie, Campbell, Robert A., Cumming, Iain A., Gillen, Kevin J., Gillespie, Jonathan, Kazemier, Bert, Kiczun, Michael, Lamont, Yvonne, Lyons, Amanda J., Maclean, John K.F., Moir, Elizabeth M., Morrow, John A., Papakosta, Marianthi, Rankovic, Zoran, Smith, Lynn
Format: Article
Language:English
Subjects:
Allosteric modulator
Allosteric Regulation
AMPA receptor
Animals
Binding Sites
Biological and medical sciences
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Glutamatergic system (aspartate and other excitatory aminoacids)
High-Throughput Screening Assays
Hit-to-lead
Humans
Indazoles - chemical synthesis
Indazoles - chemistry
Indazoles - pharmacology
Medical sciences
Microsomes - metabolism
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Protein Structure, Tertiary
Rats
Receptors, AMPA - chemistry
Receptors, AMPA - metabolism
SBDD
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacology
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Summary:Starting from an HTS hit, the evolution of lead compound 22, a positive allosteric modulator of the AMPA receptor is described using structure based drug design. Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.07.138