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

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