Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma

Lagu, Bharat; Gerchak, Chrissy; Pan, Meng; Hou, Cuifen; Singer, Monica; Malaviya, Ravi; Matheis, Michele; Olini, Gil; Cavender, Druie; Wachter, Michael P.

doi:10.1016/j.bmcl.2007.01.115

Cited by 28 publications

(18 citation statements)

References 19 publications

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“…A number of other companies including GSK [118,119] , Johnson & Johnson [120][121][122][123][124] and Astra Zeneca [125] have also disclosed CCR2 inhibitors ( Figure 2 , compounds 12 to 14). Extensive SAR converted a weak CCR2 inhibitor (IC 50 5.3 µM) identified by high-throughput screening into a more potent antagonist with an IC 50 of 50 nM [117] .…”

Section: Ccr2 Antagonistsmentioning

confidence: 96%

Chemokine receptor antagonists: Part 1

Pease

Horuk

2009

Expert Opinion on Therapeutic Patents

103

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Section: Ccr2 Antagonistsmentioning

confidence: 96%

Chemokine receptor antagonists: Part 1

Pease

Horuk

2009

Expert Opinion on Therapeutic Patents

103

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“…Similarly, scientists from Johnson & Johnson recently described compounds from their CCR2 discovery program that had modest activity for CCR5 exemplified by compound 3n (Fig. 3) with IC 50 values of 20 nM and 1 M respectively for CCR2 and CCR5 [86].…”

Section: Dual Antagonists Of Ccr2 and Ccr5mentioning

confidence: 97%

Small Molecule Antagonists of Chemokine Receptors - is Promiscuity a Virtue?

Pease¹,

Horuk

2010

CTMC

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A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly "druggable" GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting. In this article, we discuss the successes and failures of chemokine receptor antagonists in the clinic and review a subset of molecules that are documented as having activity at two or more chemokine receptors. It may be that a more permissive approach, targeting several chemokine receptors with a single molecule will provide the next generation of anti-inflammatory drugs.

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“…163 US28 ligands include compounds 45 , 180 46 , 47 , 181 48 , 182 49 , 181 50 , 184 51 , 185 and 52 . 186 CCR2 ligands include compounds 53 , 173 54 , 174 55 , 175 56 , 177 57 , 58 , 45 59 , 178 and CCR9 ligands 60 . 179 Interactions between the ligands and specific residues derived from X-ray structures (bold), mutation studies (gray), or models without support from experimental data (gray italics) are depicted by a dotted line, interacting groups are surrounded by a dotted line, and key features are summarized by a solid box.…”

Section: Crystal Structure-based Analysis Of the Effects Of Site-dirementioning

confidence: 99%

Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

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Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma

Cited by 28 publications

References 19 publications

Chemokine receptor antagonists: Part 1

Chemokine receptor antagonists: Part 1

Small Molecule Antagonists of Chemokine Receptors - is Promiscuity a Virtue?

Structural Analysis of Chemokine Receptor–Ligand Interactions

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