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

Abstract

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.

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

“…Our results are in line with other reports showing that allergic airway disease was not impaired in mice deficient for CCR4 or after treatment with anti-CCR4 (21,22). However, these findings conflict with other studies showing that CCR4 and its interaction with respective chemokines CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine) play a role in allergic inflammation (20,(36)(37)(38)(39)(40)(41)(42)(43). These conflicting results on the role of CCR4 in allergy remain to be elucidated, but may be due to different experimental protocols and animals employed.…”

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

“…The chemotaxis assay was performed as described previously [35]. Six hundred microliter of chemotaxis buffer [RPMI-1640 medium containing 0.5 w/v% fatty acid-free BSA (Sigma-Aldrich, St. Louis, Mo., USA)] containing chemokines was placed in the lower wells of a transwell system (24-well plate).…”

“…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]. Subsequent medicinal chemistry efforts led to the discovery of a small molecular compound, K777, as a potential candidate.…”

Regulation of Chemokine- Receptor Interactions and Functions

“…The C-terminal alpha helix of CXCL8, in addition to some basic residues located within the N-loop, is critical for GAG binding [102,103] due to its positive electrostatic charge. This binding is mediated by basic amino acids (Arg, Lys, His) core residues and by other secondary residues across its sequence (as shown in Figure 4) [41,104]. Targeted substitution of these basic residues for alanine residues reduced in vivo neutrophil recruitment to the peritoneum [8,32], but increased recruitment to the lungs [32,105].…”