Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

Zheng, Changsheng; Cao, Ganfeng; Xia, Michael; Feng, Hao; Glenn, J. R.; Anand, Rajan; Zhang, Ke; Huang, Taiyi; Wang, Anlai; Kong, Ling; Li, Mei; Galya, Laurine; Hughes, Robert; Devraj, Rajesh; Morton, Phillip A.; Rogier, D. Joseph; Covington, Maryanne; Baribaud, Fred; Shin, Niu; Scherle, Peggy; Diamond, Sharon; Yeleswaram, Swamy; Vaddi, Kris; Newton, Robert; Hollis, Greg; Friedman, Steven; Metcalf, Brian W.; Xue, Chu‐Biao

doi:10.1016/j.bmcl.2011.01.015

Cited by 29 publications

(22 citation statements)

References 26 publications

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“…Incyte also recently disclosed INCB10820/PF-4178903, which was jointly developed with Pfizer and is a dual CCR2/CCR5 antagonist with an IC 50 for inhibition of CCR2 and CCR5 binding of 3.0 and 5.3 nM, respectively (9, Figure 4). 116 This compound is structurally identical to the Merck compound 7 except that it has a trifluoromethylpyridinepiperazine ring that replaces the trifluoromethylnaphthyridine group in 7 (7 and 9, Figure 4). Compound 9 was initially selected as a clinical candidate based on its potency and favorable pharmacokinetic properties; however, it had some cardiovascular liabilities, an affinity of 1.7 μM for hERG (an ion channel associated with cardiovascular adverse events) that precluded further clinical development.…”

Section: ■ Chemokine Receptor Antagonistsmentioning

confidence: 96%

Chemokine Receptor Antagonists

Pease

Horuk

2012

J. Med. Chem.

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Section: ■ Chemokine Receptor Antagonistsmentioning

confidence: 96%

Chemokine Receptor Antagonists

Pease

Horuk

2012

J. Med. Chem.

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“…So, structural information of CCR2 and CCR5 can be useful and essential for providing insights about targeting these receptors. Two recent studies have reported the use of dual antagonists targeting both CCR2 and CCR5 [21], [22].…”

Section: Introductionmentioning

confidence: 99%

Structural Insights from Binding Poses of CCR2 and CCR5 with Clinically Important Antagonists: A Combined In Silico Study

2012

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Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å), we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2) and Glu283 (CCR5) are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design.

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“…However, the combination of CXCL12 (homeostatic chemokine) and CCL2 (inflammatory chemokine) blockade prevented proteinuria in mice with diabetic nephropathy [84]. With this idea, recent studies have used a dual antagonist to target both CCR2 and CCR5 [76,85,86] although none of them have been tested in clinical studies yet. The difficulty in targeting these receptors is due to both the complexity of unraveling their structure and to the functional redundancy of the chemokine system and the formation of homo-and hetero-oligomers between different chemokines and chemokines receptors.…”

Section: Chemokine Receptorsmentioning

confidence: 96%