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

…, E Ballini, DM Bradley, BD Bax, BP Clarke…

Index: Ward, Simon E.; Harries, Mark; Aldegheri, Laura; Austin, Nigel E.; Ballantine, Stuart; Ballini, Elisa; Bradley, Daniel M.; Bax, Benjamin D.; Clarke, Brian P.; Harris, Andrew J.; Harrison, Stephen A.; Melarange, Rosemary A.; Mookherjee, Claudette; Mosley, Julie; Dal Negro, Gianni; Oliosi, Beatrice; Smith, Kathrine J.; Thewlis, Kevin M.; Woollard, Patrick M.; Yusaf, Shahnaz P. Journal of Medicinal Chemistry, 2011 , vol. 54, # 1 p. 78 - 94

Full Text: HTML

Citation Number: 33

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 ...