Optimization of 2-aminothiazole derivatives as CCR4 antagonists

Wang, Xuemei; Xu, Feng; Xu, Qingge; Mahmud, Hossen; Houze, Jonathan B.; Zhu, Linchao; Akerman, Michelle; Tonn, George; Tang, Liang; McMaster, Brian E.; Dairaghi, Daniel J.; Schall, Thomas J.; Collins, Tassie L.; Medina, Julio C.

doi:10.1016/j.bmcl.2006.01.126

Cited by 33 publications

(14 citation statements)

References 7 publications

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“…Previous attempts to develop CCR4 antagonists have revealed that racemic thiazolidinones display good receptor affinity but lack sufficient drug-like properties in vivo. Although switching the thiazolidinone core to lactam, pyrimidine, isoxazole, and pyrazole produced better drug-like properties, only molecules with isoxazole retained potency (29,30).…”

Section: If Ccr4mentioning

confidence: 99%

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Bayry

Tchilian

Davies

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

100

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Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4.

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Section: If Ccr4mentioning

confidence: 99%

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Bayry

Tchilian

Davies

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

100

View full text Add to dashboard Cite

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“…As a result, a variety of compounds, such as naphthalene-sulfonamide derivatives [16] , 2-aminothiazole derivatives [17] and pyrimidine derivatives [18][19][20] , have been reported. All of these compounds were demonstrated to possess inhibitory activity on CCL17/ CCL22 binding to CCR4 and on in vitro chemotaxis of CCR4 expressing cells toward CCL17/CCL22.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of the New Orally Active CCR4 Antagonist K327 on CCR4+CD4+ T Cell Migration into the Lung of Mice with Ovalbumin-Induced Lung Allergic Inflammation

Sato

Komai²,

Iwase³

et al. 2008

Pharmacology

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CC chemokine receptor 4 (CCR4) is expressed on Th2 cells, found in inflamed tissues of allergic diseases, and is therefore suspected to be involved in the pathogenesis of allergic diseases by controlling Th2 cell migration into inflamed tissues. The aim of the present study was to investigate the inhibitory effect of a selective CCR4 antagonist, K327 [6-cyclopropancarbonyl-4-(2,4-dichlorobenzylamino)-2-(4-[2-(piperidin-1-yl)ethyl] piperazin-1-yl)-7,8-dihydro-5H-pyrido (4,3-d)pyrimidine], on the recruitment of CCR4+CD4+ T cells to the airway of mice with ovalbumin-induced allergic airway inflammation. K327 was administered to mice in which CCR4+CD4+ T cell accumulation was elicited by multiple inhalations of aerosolized ovalbumin. K327 significantly and dose-dependently inhibited the recruitment of CCR4+CD4+ T cells with an ID₅₀value of 44 mg/kg, p.o. twice daily. The antiasthmatic potential of K327 was also demonstrated by the fact that K327 suppressed the elevation of Th2 cytokines and airway eosinophilia. These results indicate that CCR4 antagonists can control in vivo migration of Th2 cells which express CCR4 and, presumably, serve as a new class of therapeutic agent for allergy.

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“…The activity was more potent than would be expected from a classical competitive antagonist of a GPCR. In general, in vitro functional assays of competitive antagonists usually require a higher ligand concentration than binding assays to obtain the maximum cellular response to the ligand, and accordingly, higher concentrations are required for a competitive GPCR antagonist to inhibit ligand-induced cellular functions than to inhibit ligand binding [28,31,33]. Indeed, a 10-fold higher concentration of CCL17 was used in the Hut78 chemotaxis assay than was used in the binding assay in the same cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, several types of compounds have been identified, including 2-aminothiazole derivatives [28], thiazolidinone derivatives [29], bipiperidine derivatives [30], quinazoline derivatives [31], pyrimidine derivatives [32,33] and pyridopyrimidine derivatives [34]. In our search for novel CCR4 antagonists, we screened our chemical library using a CCL17 binding assay and finally identified pyrimidine moieties as lead compounds [35].…”

Section: Introductionmentioning

confidence: 99%

Internalization of CCR4 and Inhibition of Chemotaxis by K777, a Potent and Selective CCR4 Antagonist

Sato

Iwase²,

Miyama³

et al. 2013

Pharmacology

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CC chemokine receptor 4 (CCR4) is a G protein-coupled receptor that regulates the chemotaxis of Th2 lymphocytes, which are key players in allergic diseases. K777 is a small compound identified in a binding assay using a CCR4 ligand, CCL17. K777 inhibited both CCL17 binding and CCL17-induced chemotaxis in Hut78 cells (IC₅₀: 57 and 8.9 nmol/l, respectively). The K777-mediated inhibition of chemotaxis was potent even in the presence of a 10-fold higher concentration of CCL17. The imaging and flow cytometric analyses revealed that K777 induced CCR4 internalization, with a ∼50% reduction of cell surface CCR4. K777 did not inhibit CXCR4-induced chemotaxis or internalization and did not bring about Ca²⁺ mobilization by itself. A Scatchard plot analysis of the binding assay using radiolabeled K777 revealed a single high-affinity binding site on the CCR4 molecule. These results indicate that K777 is a selective CCR4 antagonist featuring the potent chemotaxis inhibition, to which the internalization-inducible ability of K777 to hide a part of cell surface CCR4 may contribute.

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Optimization of 2-aminothiazole derivatives as CCR4 antagonists

Cited by 33 publications

References 7 publications

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Inhibitory Effect of the New Orally Active CCR4 Antagonist K327 on CCR4+CD4+ T Cell Migration into the Lung of Mice with Ovalbumin-Induced Lung Allergic Inflammation

Internalization of CCR4 and Inhibition of Chemotaxis by K777, a Potent and Selective CCR4 Antagonist

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