2. Academic Validation
  3. Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators

Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators

  • J Med Chem. 2011 Jan 13;54(1):78-94. doi: 10.1021/jm100679e.
Simon E Ward 1,  Mark Harries,  Laura Aldegheri,  Nigel E Austin,  Stuart Ballantine,  Elisa Ballini,  Daniel M Bradley,  Benjamin D Bax,  Brian P Clarke,  Andrew J Harris,  Stephen A Harrison,  Rosemary A Melarange,  Claudette Mookherjee,  Julie Mosley,  Gianni Dal Negro,  Beatrice Oliosi,  Kathrine J Smith,  Kevin M Thewlis,  Patrick M Woollard,  Shahnaz P Yusaf
Affiliations

Affiliation

  • 1 School of Life Sciences, University of Sussex, Brighton, United Kingdom. [email protected]
PMID: 21128618 DOI: 10.1021/jm100679e
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.

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