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BioAssay: AID 640525

Antagonist activity at 20% inactivated human sodium channel Nav1.7 expressed in human HEK293 cells by patch-clamp electrophysiological assay

Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified more ..
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 Tested Compounds
 Tested Compounds
All(26)
 
 
Active(13)
 
 
Unspecified(13)
 
 
 Tested Substances
 Tested Substances
All(26)
 
 
Active(13)
 
 
Unspecified(13)
 
 
AID: 640525
Data Source: ChEMBL (797973)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2012-09-09
Modify Date: 2014-08-24

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Sodium channel protein type 9 subunit alpha; AltName: Full=Neuroendocrine sodium channel; Short=hNE-Na; AltName: Full=Peripheral sodium channel 1; Short=PN1; AltName: Full=Sodium channel protein type IX subunit alpha; AltName: Full=Voltage-gated sodium channel subunit alpha Nav1.7
Description ..   
Protein Family: Sodium ion transport-associated
Comment ..   

Gene:SCN9A     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 13
Description:
Title: Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.

Abstract: Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.
(PMID: 22209205)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Functional
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Assay Cell Type: HEK293
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2IC50 activity commentIC50 activity commentString
3IC50 standard flagIC50 standard flagInteger
4IC50 qualifierIC50 qualifierString
5IC50 published valueIC50 published valueFloatmM
6IC50 standard valueIC50 standard valueFloatnM
7IC50 data validityIC50 data validityString
8IC50 binding domainsIC50 binding domainsString
9IC50 activity commentIC50 activity commentString
10IC50 standard flagIC50 standard flagInteger
11IC50 qualifierIC50 qualifierString
12IC50 published valueIC50 published valueFloatμM
13IC50 standard valueIC50 standard valueFloatnM
14IC50 data validityIC50 data validityString
15IC50 binding domainsIC50 binding domainsString

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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