Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation

Procopiou, Panayiotis A.; Ford, Alison J.; Graves, Rebecca H.; Hall, David A.; Hodgson, Simon T.; Lacroix, Yannick M. L.; Needham, Deborah; Slack, Robert J.

doi:10.1016/j.bmcl.2012.02.104

Cited by 20 publications

(23 citation statements)

References 18 publications

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“…In this study we used a range of protein and small molecule ligands of the CCR4 receptor to probe aspects of its function. Compound 1 and Compound 2 are representative of a class of lipophilic amines, and Compound 3 and Compound 4 are representative of a class of arylsulfonamides (Procopiou et al, 2012), all of which were synthesized by Respiratory Therapy Area Unit Medicinal Chemistry, GlaxoSmithKline (Supplementary data Fig. S1).…”

Section: Methodsmentioning

confidence: 99%

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists

Ajram

Begg

Slack

et al. 2014

European Journal of Pharmacology

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The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.

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Section: Methodsmentioning

confidence: 99%

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists

Ajram

Begg

Slack

et al. 2014

European Journal of Pharmacology

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“…Since then there have been many reports of CCR4 antagonists that can grouped into two main chemical categories. The first is a collection of lipophilic heteroarenes from Bristol Myers Squibb, Astellas and Daiichi Sankyo and the second is a range of aryl sulphonamides from Astra Zeneca, Ono and GlaxoSmithKline ( Andrews et al, 2007 , Banfield et al, 2010 , Burdi et al, 2007 , Cahn et al, 2013 , Kuhn et al, 2007 , Nakagami et al, 2010a , Nakagami et al, 2010b , Nakagami et al, 2009 , Procopiou et al, 2013 , Procopiou et al, 2012 , Purandare et al, 2007 , Solari et al, 2014 , Yokoyama et al, 2009 , Yokoyama et al, 2008 , Zhao et al, 2009 ). Some pertinent structures from these studies are shown in Fig.…”

Section: Blockade Of Ccr4 In the Treatment Of Diseasementioning

confidence: 99%

Targeting chemokine receptors in disease – a case study of CCR4

Solari

Pease

2015

European Journal of Pharmacology

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Since their early 1990s, the chemokine receptor family of G protein-coupled receptors (GPCRs) has been the source of much pharmacological endeavour. Best known for their key roles in recruiting leukocytes to sites of infection and inflammation, the receptors present themselves as plausible drug targets for therapeutic intervention. In this article, we will focus our attention upon CC Chemokine Receptor Four (CCR4) which has been implicated in diseases as diverse as allergic asthma and lymphoma. We will review the discovery of the receptors and their ligands, their perceived roles in disease and the successful targeting of CCR4 by both small molecule antagonists and monoclonal antibodies. We will also discuss future directions and strategies for drug discovery in this field.

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“…A number of companies have described CCR4 antagonists, and these were recently reviewed (Pease and Horuk, 2009). All of these molecules are still preclinical, but GSK recently disclosed a series of indazole sulfonamides (Procopiou et al, 2012) and identified a clinical development compound (GSK2239633) that has entered phase I clinical trials, presumably for allergy and asthma (Fig. 13).…”

mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

et al. 2013

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Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation

Cited by 20 publications

References 18 publications

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists

Targeting chemokine receptors in disease – a case study of CCR4

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

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