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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

2010; American Chemical Society; Volume: 54; Issue: 1 Linguagem: Inglês

10.1021/jm100679e

1520-4804

Simon E. Ward, Mark H Harries, Laura Aldegheri, Nigel Austin, Stuart P. Ballantine, Elisa Ballini, Daniel M. Bradley, B.D. Bax, Brian Clarke, A. I. Harris, Stephen A. Harrison, Rosemary A. Melarange, Claudette Mookherjee, J. Mosley, Gianni Dal Negro, Beatrice Oliosi, Kathrine J. Smith, Kevin M. Thewlis, P.M. Woollard, Shahnaz P. Yusaf,

Pharmacological Receptor Mechanisms and Effects

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.