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.
School of Life Sciences, University of Sussex, Brighton, United Kingdom. simon.ward@sussex.ac.uk
Simon E
SE
Ward
Mark
M
Harries
Laura
L
Aldegheri
Nigel E
NE
Austin
Stuart
S
Ballantine
Elisa
E
Ballini
Daniel M
DM
Bradley
Benjamin D
BD
Bax
Brian P
BP
Clarke
Andrew J
AJ
Harris
Stephen A
SA
Harrison
Rosemary A
RA
Melarange
Claudette
C
Mookherjee
Julie
J
Mosley
Gianni
G
Dal Negro
Beatrice
B
Oliosi
Kathrine J
KJ
Smith
Kevin M
KM
Thewlis
Patrick M
PM
Woollard
Shahnaz P
SP
Yusaf
D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D004285:Dogs; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D018408:Patch-Clamp Techniques; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D013552:Swine; D013556:Swine, Miniature
D007191:Indazoles; D008024:Ligands; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D002118:Calcium