Novel, Acidic CCR2 Receptor Antagonists: From Hit to Lead

Zou, Dingquan; Zhai, H.-X.; Eckman, Joseph; Higgins, Paul J.; Gillard, Michel; Knerr, Laurent; Carré, Stéphane; Pasau, Patrick; Collart, Philippe; Grassi, Jeffrey M.

doi:10.2174/157018007780077381

Cited by 17 publications

(16 citation statements)

References 2 publications

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“…All antagonists displaced 125 I-CCL2 from the receptor ( Fig. 3A; Table 2) with affinities similar to previously reported data (Mirzadegan et al, 2000;Brodmerkel et al, 2005;Zou et al, 2007;Buntinx et al, 2008;Cherney et al, 2008;Moree et al, 2008). BMS22, RS504393, and Teijin were also able to displace (Table 2).…”

Section: Discussionsupporting

confidence: 88%

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Multiple Binding Sites for Small-Molecule Antagonists at the CC Chemokine Receptor 2

et al. 2013

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The chemokine receptor CCR2 is a G protein-coupled receptor that is activated primarily by the endogenous CC chemokine ligand 2 (CCL2). Many different small-molecule antagonists have been developed to inhibit this receptor, as it is involved in a variety of diseases characterized by chronic inflammation. Unfortunately, all these antagonists lack clinical efficacy, and therefore a better understanding of their mechanism of action is warranted. In this study, we examined the pharmacological properties of smallmolecule CCR2 antagonists in radioligand binding and functional assays. Six structurally different antagonists were selected for this study, all of which displaced the endogenous agonist 125

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Section: Discussionsupporting

confidence: 88%

“…INCB3344, JNJ-27141491, and CCR2-RA- [R] were synthesized in-house as described previously (Xue et al, 2004;Brodmerkel et al, 2005;Zou et al, 2007;Doyon et al, 2008 …”

Section: Methodsmentioning

confidence: 99%

Multiple Binding Sites for Small-Molecule Antagonists at the CC Chemokine Receptor 2

et al. 2013

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“…Substitution of the cycloalkyl group by a phenyl group ( 9 ) led to a great loss of CCR2 affinity (39% displacement at 1 μM), consistent with previously reported values showing a decreased affinity for an almost similar pair of compounds. 36 Yet this substitution only led to a 3-fold decrease in CCR1 affinity ( K i of 162 nM), thus showing much higher selectivity for CCR1. Next, we explored the effect of N -aryl modifications in both affinity and selectivity (compounds 10 – 17 ), specifically the effect of para and meta substituents.…”

Section: Resultsmentioning

confidence: 97%

“…Previous modifications to the vinylogous carboxylic acid functionality in CCR2 showed detrimental effects in binding affinity. 29,36 Indeed, mutagenesis and structural studies have shown crucial interactions of the hydroxyl and the two carbonyl groups with Glu310 8x48 , Lys311 8x49 , and Phe312 8x50 (residues according to structure-based Ballesteros–Weinstein numbering 37 ) in CCR2. 24,28 Sequence alignment of CCR1 and CCR2 (Supporting Information, Figure S2) and our docking study (Figure 2) suggest similar interactions in CCR1, as only position 8.49 differs (arginine in CCR1 and lysine in CCR2).…”

Section: Resultsmentioning

confidence: 99%

Pyrrolone Derivatives as Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2

et al. 2018

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The recent crystal structures of CC chemokine receptors 2 and 9 (CCR2 and CCR9) have provided structural evidence for an allosteric, intracellular binding site. The high conservation of residues involved in this site suggests its presence in most chemokine receptors, including the close homologue CCR1. By using [3H]CCR2-RA-[R], a high-affinity, CCR2 intracellular ligand, we report an intracellular binding site in CCR1, where this radioligand also binds with high affinity. In addition, we report the synthesis and biological characterization of a series of pyrrolone derivatives for CCR1 and CCR2, which allowed us to identify several high-affinity intracellular ligands, including selective and potential multitarget antagonists. Evaluation of selected compounds in a functional [35S]GTPγS assay revealed that they act as inverse agonists in CCR1, providing a new manner of pharmacological modulation. Thus, this intracellular binding site enables the design of selective and multitarget inhibitors as a novel therapeutic approach.

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“…CCL2 was purchased from PeproTech (Rocky Hill, NJ). INCB3344, JNJ-27141491, and CCR2-RA- [R] were synthesized according to published methods (Xue et al, 2004;Brodmerkel et al, 2005;Zou et al, 2007;Doyon et al, 2008). SD-24 (sulfonamide derivative #24 from Peace et al, 2010) was synthesized in-house, according to procedures described previously (Peace et al, 2010 CCR5 was cloned in-house from a leukocyte cDNA library, whereas WT FLAG-tagged CCR2 cDNA was kindly provided by Dr. Tim Wells (GlaxoSmithKline, London, UK).…”

Section: Methodsmentioning

confidence: 99%

Discovery and Mapping of an Intracellular Antagonist Binding Site at the Chemokine Receptor CCR2

et al. 2014

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The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divided into two groups with most likely two topographically distinct binding sites. The aim of the current study was to identify the binding site of one such group of ligands, exemplified by three allosteric antagonists, CCR2-RA-[R], JNJ-27141491, and SD-24. We first used a chimeric CCR2/CCR5 receptor approach to obtain insight into the binding site of the allosteric antagonists and additionally introduced eight single point mutations in CCR2 to further characterize the putative binding pocket. All constructs were studied in radioligand binding and/or functional IP turnover assays, providing evidence for an intracellular binding site for CCR2-RA-[R], JNJ-27141491, and SD-24. For CCR2-RA-[R] the most important residues for binding were found to be the highly conserved tyrosine Y 7.53 and phenylalanine F 8.50 of the NPxxYx (5,6) F motif, as well as V 6.36 at the bottom of TM-VI and K 8.49 in helix-VIII. These findings demonstrate for the first time the presence of an allosteric intracellular binding site for CCR2 antagonists. This contributes to an increased understanding of the interactions of diverse ligands at CCR2 and may allow for a more rational design of future allosteric antagonists.

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Novel, Acidic CCR2 Receptor Antagonists: From Hit to Lead

Cited by 17 publications

References 2 publications

Multiple Binding Sites for Small-Molecule Antagonists at the CC Chemokine Receptor 2

Multiple Binding Sites for Small-Molecule Antagonists at the CC Chemokine Receptor 2

Pyrrolone Derivatives as Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2

Discovery and Mapping of an Intracellular Antagonist Binding Site at the Chemokine Receptor CCR2

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