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rdf:type |
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lifeskim:mentions |
umls-concept:C0010424,
umls-concept:C0022009,
umls-concept:C0023175,
umls-concept:C0072899,
umls-concept:C0456387,
umls-concept:C1158478,
umls-concept:C1446409,
umls-concept:C1521840,
umls-concept:C1705422,
umls-concept:C1709060,
umls-concept:C1880355,
umls-concept:C2698650
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pubmed:issue |
1
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pubmed:dateCreated |
2011-9-15
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pubmed:databankReference |
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pubmed:abstractText |
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AldegheriLauraL,
pubmed-author:AustinNigel ENE,
pubmed-author:BallantineStuartS,
pubmed-author:BalliniElisaE,
pubmed-author:BaxBenjamin DBD,
pubmed-author:BradleyDaniel MDM,
pubmed-author:ClarkeBrian PBP,
pubmed-author:Dal NegroGianniG,
pubmed-author:HarriesMarkM,
pubmed-author:HarrisAndrew JAJ,
pubmed-author:HarrisonStephen ASA,
pubmed-author:MelarangeRosemary ARA,
pubmed-author:MookherjeeClaudetteC,
pubmed-author:MosleyJulieJ,
pubmed-author:OliosiBeatriceB,
pubmed-author:SmithKathrine JKJ,
pubmed-author:ThewlisKevin MKM,
pubmed-author:WardSimon ESE,
pubmed-author:WoollardPatrick MPM,
pubmed-author:YusafShahnaz PSP
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
78-94
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pubmed:meshHeading |
pubmed-meshheading:21128618-Allosteric Regulation,
pubmed-meshheading:21128618-Animals,
pubmed-meshheading:21128618-Calcium,
pubmed-meshheading:21128618-Crystallography, X-Ray,
pubmed-meshheading:21128618-Dogs,
pubmed-meshheading:21128618-High-Throughput Screening Assays,
pubmed-meshheading:21128618-Humans,
pubmed-meshheading:21128618-Indazoles,
pubmed-meshheading:21128618-Ligands,
pubmed-meshheading:21128618-Macaca fascicularis,
pubmed-meshheading:21128618-Male,
pubmed-meshheading:21128618-Microsomes, Liver,
pubmed-meshheading:21128618-Models, Molecular,
pubmed-meshheading:21128618-Molecular Conformation,
pubmed-meshheading:21128618-Patch-Clamp Techniques,
pubmed-meshheading:21128618-Protein Multimerization,
pubmed-meshheading:21128618-Rats,
pubmed-meshheading:21128618-Rats, Sprague-Dawley,
pubmed-meshheading:21128618-Receptors, AMPA,
pubmed-meshheading:21128618-Recombinant Proteins,
pubmed-meshheading:21128618-Solubility,
pubmed-meshheading:21128618-Structure-Activity Relationship,
pubmed-meshheading:21128618-Swine,
pubmed-meshheading:21128618-Swine, Miniature
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pubmed:year |
2011
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pubmed:articleTitle |
Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators.
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pubmed:affiliation |
School of Life Sciences, University of Sussex, Brighton, United Kingdom. simon.ward@sussex.ac.uk
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pubmed:publicationType |
Journal Article,
In Vitro
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