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.
MeSH terms
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Allosteric Regulation
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Animals
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Calcium / metabolism
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Crystallography, X-Ray
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Dogs
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High-Throughput Screening Assays
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Humans
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In Vitro Techniques
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Indazoles / chemical synthesis*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Ligands
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Macaca fascicularis
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Male
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Conformation
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Patch-Clamp Techniques
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Protein Multimerization
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Rats
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Rats, Sprague-Dawley
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Receptors, AMPA / chemistry
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Receptors, AMPA / physiology*
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Recombinant Proteins / chemistry
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Solubility
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Structure-Activity Relationship
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Swine
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Swine, Miniature
Substances
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Indazoles
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Ligands
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Receptors, AMPA
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Recombinant Proteins
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Calcium
Associated data
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PDB/2XX7
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PDB/2XX8
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PDB/2XX9
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PDB/2XXH
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PDB/2XXI