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

Ward, Simon ORCID: https://orcid.org/0000-0002-8745-8377, Harries, Mark, Aldegheri, Laura, Austin, Nigel E., Ballantine, Stuart, Ballini, Elisa, Bradley, Daniel M., Bax, Benjamin ORCID: https://orcid.org/0000-0003-1940-3785, 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. and Yusaf, Shahnaz P. 2011. Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators. Journal of Medicinal Chemistry 54 (1) , pp. 78-94. 10.1021/jm100679e

Full text not available from this repository.

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
ISSN:	0022-2623
Last Modified:	23 Oct 2022 12:59
URI:	https://orca.cardiff.ac.uk/id/eprint/109336

Citation Data

Cited 59 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item