Bookmark and Share
BioAssay: AID 771599

Displacement of [125I]-CCL2 from human CCR2 receptor expressed in human U2OS cell membrane at 1 uM 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 ..
_
   
 Tested Compounds
 Tested Compounds
All(6)
 
 
Unspecified(6)
 
 
 Tested Substances
 Tested Substances
All(6)
 
 
Unspecified(6)
 
 
 Related BioAssays
 Related BioAssays
AID: 771599
Data Source: ChEMBL (983388)
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
1Inhibition activity commentInhibition activity commentString
2Inhibition standard flagInhibition standard flagInteger
3Inhibition qualifierInhibition qualifierString
4Inhibition published valueInhibition published valueFloat%
5Inhibition standard valueInhibition standard valueFloat%

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