A Novel, Selective, and Orally Available Antagonist for CC Chemokine Receptor 3

Abstract

CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/ eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4 ϩ T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.Eosinophils play a crucial role in allergic diseases such as bronchial asthma and allergic rhinitis (Durham and Kay, 1985;Terada et al., 1994). CCR3, a seven-transmembranespanning G protein-coupled receptor, is a major chemokine receptor expressed on allergic inflammatory cells including not only eosinophils but also basophils, mast cells, and T helper 2-type CD4 ϩ cells (Combadiere et al., 1995;Post et al., 1995;Sabroe et al., 1998). This receptor has been identified in humans, monkeys, mice, rats, and guinea pigs (GarciaZepeda et al., 1996;Forssmann et al., 1997;Sallusto et al., 1997;Zhang et al., 2002). Human CCR3 binds multiple chemokine ligands such as CCL11/eotaxin, CCL24/eotaxin-2, CCL26/eotaxin-3, and CCL13/MCP-4 with high affinity, whereas CCR3 binds CCL5/regulated on activation normal T cell expressed and secreted and CCL7/MCP-3 with lower affinity (Forssmann et al., 1997;Stellato et al., 1997;Doucet et al., 1998). CCR3 ligands are produced by multiple cell types, including lung and mucosal fibroblast cells, bronchial epithelial cells, vascular endothelial cells, smooth muscle cells, macrophages, mast cells, and eosinophils (Lamkhioued et al., 1997;Lilly et al., 1997;Shinkai et al., 1999;Hirst et al., 2002;Menzies-Gow et al., 2004). The binding of CCR3 ligands to CCR3 on the surface of eosinophils causes a transient increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) that activates several signal pathways, including actin polymerization (Elsner et al., 1996). With activation of the intracellular motile apparatus, eosinophils undergo shape change

Small molecule antagonists for chemokine CCR3 receptors

“…In cynomolgus monkeys, 4a was able to reduce the airway eosinophilia that was induced by segmental bronchoprovocation with the CCR3 ligand CCL11. 40 This compound was also reported to inhibit the infiltration of other CCR3-expressing cells, while the numbers of neutrophils and monocytes in the lung were not affected. Antagonist 4c inhibited the infiltration of eosinophils (but not neutrophils and mononuclear cells) into the airways of intraperitoneally sensitized mice after allergen-challenge by inhalation of aerosolized ovalbumin.…”

“…AstraZeneca patented 4-phenoxy-piperidine (34) 65 and -bipiperidine (35) 66 derivatives as dual antagonists for both CCR3 and the histamine H1 receptor, while Novartis described piperidinylideneacetamide analogues (36) 67 and piperazine derivatives (37) 68 as CCR3 receptor antagonists with binding IC 50 values in the range of 56-290 nM. Other piperidinyl and piperazinyl based antagonists, most of which equipped with urea-like moieties, were patented by F. Hoffmann-La Roche (38)(39)(40). 69 These compounds were reported to inhibit the recruitment of eosinophils induced by CCR3 chemokines.…”

“…[40][41][42] Several heteroaromatic substituents were investigated, with the substituents shown in Table II (4a and 4b) representing some of the most potent CCR3 antagonists. 40,41 These compounds showed binding IC 50 values of 7.6 and 3.0 nM, respectively, and also exhibited antagonizing effects in functional assays. CCL11-induced intracellular calcium flux was inhibited by 4a and 4b with IC 50 values of 8.0 and 5.4 nM, respectively, and chemotaxis with IC 50 values of 24 and 19.9 nM, respectively.…”

Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis

“…Thus, CCR3 [119] and CD123 (IL-3 receptor α chain) [120] have been selected as constant expression and identification markers for basophils to distinguish these cells from CD63, the activation marker. Because CCR3 has also been observed on eosinophils [121] and a small proportion of CD4 + T cells [122] , this protein is not the unique marker for basophils. Similarly, CD123 has been identified on plasmacytoid DCs [123] and plasmacytoid monocytes [124] ; thus, this protein is not a unique marker for basophils either.…”

Origin, regulation and physiological function of intestinal oeosinophils

“…Collectively, these studies and others have provided the impetus for the development of therapeutic agents aimed at blocking the action of eotaxins and/or CCR3. As such, small molecule inhibitors of CCR3 and a humanized anti-human eotaxin-1 antibody have been developed [66][67][68][69].…”