Chemokine Receptor Antagonists

Pease, James E.; Horuk, Richard

doi:10.1021/jm300682j

Cited by 89 publications

(64 citation statements)

References 221 publications

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“…So far, many chemokine receptor antagonists have been developed, but most of these have failed in clinical trials for the treatment of several inflammatory diseases except for two approved drugs for noninflammatory diseases: a CCR5 inhibitor, which is used to treat HIV, and a CXCR4 antagonist, which serves as a haematopoietic stem cell mobiliser. 12 One of the most important reasons for these failures is target redundancy (one chemokine can target several receptors and vice versa) in complex inflammatory diseases. The pathophysiology of AH, especially the severe form, is very complex, with elevations in the levels of multiple chemokines, including IL-8, Gro-α, CXCL5, CXCL6, CXCL10, CCL2 and CCL20, among others.…”

Section: Bin Gao Mingjiang Xumentioning

confidence: 99%

Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?

Gao

2014

Gut

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Section: Bin Gao Mingjiang Xumentioning

confidence: 99%

Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?

Gao

2014

Gut

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“…Moreover, CCR2 pharmacological inhibition has been shown to reduce adipose tissue inflammation and improve metabolic parameters (22,43,44,54). Despite extensive efforts to identify pharmaceutically suitable CCR2 drug candidates, to date only one CCR2 antagonist, orally active CCX140-B, has been shown to improve glycemic parameters (hemoglobin A 1c and fasting blood glucose) in diabetic patients (16,35).…”

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confidence: 99%

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

Sullivan

Miao

Dairaghi

et al. 2013

American Journal of Physiology-Renal Physiology

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. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol 305: F1288 -F1297, 2013. First published August 28, 2013 doi:10.1152/ajprenal.00316.2013.-Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.

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“…With the benefit of hindsight, the selection of psoriasis as an arena in which to test CXCR3 blockade is questionable. The supporting evidence has been dubbed to be from "guilt by association studies" [28], since by virtue of their expression, CXCR3 and its ligands were assumed to play a principal role in the disease. However, the precise role of CXCR3 in psoriasis is poorly understood.…”

Section: Cxcr3 and Its Blockade In Disease -Success And Failurementioning

confidence: 99%

Designing small molecule CXCR3 antagonists

Pease

2016

Expert Opinion on Drug Discovery

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IntroductionBy virtue of its specificity for chemokines induced in Th1-associated pathologies, CXCR3 has attracted considerable attention as a target for therapeutic intervention.Several pharmacologically distinct small molecules with in vitro and in vivo potency have been described in the literature, although to date, none have shown efficacy in clinical trials. Areas coveredIn this article I will outline the rationale for targeting CXCR3 and discuss the potential pitfalls in targeting receptors in poorly understood areas of chemokine biology. I will also cover emerging therapeutic areas outside of the "traditional" Th1 arena in which CXCR3 antagonists may ultimately bear fruit. The design of recently discovered small molecules targeting CXCR3 will be also be discussed. Expert OpinionCXCR3 and its ligands appear to play roles in a multitude of diverse diseases in humans. In vitro studies suggest that CXCR3 is inherently "druggable" and that potent, efficacious small molecules targeting CXCR3 antagonists will find a clinical niche. However, the well-trodden path to failure of small molecule chemokine 2 receptor antagonists in clinical trials suggests that a cautious approach should be undertaken. Ideally, unequivocal evidence elucidating the precise role of CXCR3 should be obtained before targeting the receptor in a particular disease cohort.

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Chemokine Receptor Antagonists

Cited by 89 publications

References 221 publications

Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?

Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

Designing small molecule CXCR3 antagonists

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