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BioAssay: AID 612180

Inhibition of fully inactivated human sodium channel Nav1.7 expressed in human HEK293 cells by patch-clamp electrophysiological assay

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties more ..
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Active(1)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Active(1)
 
 
Unspecified(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 612180
Data Source: ChEMBL (762191)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2012-04-30
Modify Date: 2013-11-17

Data Table ( Complete ):           Active    All
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 Compound: 1
Description:
Title: Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain.

Abstract: Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.
(PMID: 21634377)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Assay Cell Type: HEK293

ChEMBL Target ID: 18061

ChEMBL Target Type: Target is a single protein chain

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2BEIBinding Efficiency Index(nM)Float
3SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatμM
10IC50 standard valueIC50 standard valueFloatnM
11IC50 data validityIC50 data validityString
12IC50 binding domainsIC50 binding domainsString

* Activity Concentration.

Data Table (Concise)
Classification
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