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
  • 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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