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Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of AMPA Receptor Positive Allosteric Modulators
journal contribution
posted on 2023-06-08, 08:43 authored by Simon E Ward, Mark Harries, Laura Aldegheri, Nigel E Austin, et alA 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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Publication status
- Published
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
ACS PublicationsExternal DOI
Issue
1Volume
54Page range
78-94Pages
17.0Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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