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

Simon E Ward, 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

Index: J. Med. Chem. 54(1) , 78-94, (2011)

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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.