Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of AMPA Receptor Positive Allosteric Modulators

Ward, Simon E, Harries, Mark, Aldegheri, Laura, Austin, Nigel E and et al, (2011) 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 of Medicinal Chemistry, 54 (1). pp. 78-94. ISSN 0022-2623

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science
Depositing User: Simon Ward
Date Deposited: 06 Feb 2012 21:04
Last Modified: 03 Oct 2012 12:35
URI: http://sro.sussex.ac.uk/id/eprint/29402
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