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BioAssay: AID 771598

Displacement of [125I]-CCL2 from human CCR2 receptor expressed in human U2OS cell membrane assessed as kinetic rate index at Ki by dual-point competition association assay relative to control

Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and more ..
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 Tested Compounds
 Tested Compounds
All(15)
 
 
Unspecified(15)
 
 
 Tested Substances
 Tested Substances
All(15)
 
 
Unspecified(15)
 
 
 Related BioAssays
 Related BioAssays
AID: 771598
Data Source: ChEMBL (983387)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2014-05-03
Modify Date: 2014-08-24

Data Table ( Complete ):           View All Data
Target
Sequence: RecName: Full=C-C motif chemokine 2; AltName: Full=HC11; AltName: Full=Monocyte chemoattractant protein 1; AltName: Full=Monocyte chemotactic and activating factor; Short=MCAF; AltName: Full=Monocyte chemotactic protein 1; Short=MCP-1; AltName: Full=Monocyte secretory protein JE; AltName: Full=Small-inducible cytokine A2; Flags: Precursor
Description ..   
Protein Family: Chemokine_CC
Comment ..   

Gene:CCL2     Related Protein 3D Structures     More BioActivity Data..
Tested Compounds:
Description:
Title: Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists.

Abstract: Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.
(PMID: 24028535)
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Ratio activity commentRatio activity commentString
2Ratio standard flagRatio standard flagInteger
3Ratio qualifierRatio qualifierString
4Ratio published valueRatio published valueFloat
5Ratio standard valueRatio standard valueFloat

Data Table (Concise)
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