Identification of Potent, Selective Non-peptide CC Chemokine Receptor-3 Antagonist That Inhibits Eotaxin-, Eotaxin-2-, and Monocyte Chemotactic Protein-4-induced Eosinophil Migration

Abstract

The recruitment of inflammatory cells into sites of inflammation is a normal physiological response designed to fight infection, remove damaged cells, and stimulate healing. However, the excessive recruitment of such cells often exacerbates tissue damage, slows healing, and in some cases leads to host death. Therefore, inhibition of inflammatory cell recruitment may be an appropriate therapeutic strategy in a number of inflammatory diseases, such as asthma, reperfusion injury, arthritis, and inflammatory bowel disease.Chemokines are a superfamily of approximately 30 distinct small secreted proteins, and additional members continue to be identified (1, 2). They are classified into two major groups, CXC and CC, based on the position of the first two of their four invariant cysteines (3). The actions of chemokines are mediated via interactions with 7-TM 1 G protein-coupled receptors on the surface of immune and inflammatory cells. To date, 18 unique chemokine receptors, including 11 CC chemokine receptors, have been cloned (4, 5).The properties of the chemokines suggest that they are essential for leukocyte trafficking and inflammatory processes and thus are important components in a number of disease states (6, 7). Eosinophils are proinflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma (8), allergic rhinitis (9), atopic dermatitis (10), and eosinophilic gastroenteritis (11). Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites, and cytokines, all of which have the potential to produce pathophysiology. Recent studies have clearly demonstrated the presence of eosinophils or eosinophil-specific products in inflamed lung biopsy tissues in human asthma (10).Although the molecular mechanism responsible for the selective infiltration of eosinophils into inflamed tissue has not been elucidated, recently the CC chemokine eotaxin was identified in guinea pig lung following antigen challenge in sensitized guinea pigs (12, 13). Furthermore, neutralizing antibodies to eotaxin in a mouse model of allergy demonstrated inhibition of eosinophil recruitment when administered before the antigen challenge (14). Five CCR3 ligands have been shown to induce eosinophil transendothelial migration using human umbilical vein endothelial cells. This migration is inhibited by pretreatment with anti-CCR3. In addition, a human lung epithelial cell line (BEAS-2B), stimulated with proinflammatory cytokines, has been shown to produce eotaxin and 16). In humans, biopsies obtained from asthmatic lung have shown increased levels of CCR3 and its ligands, eotaxin, eotaxin-2, RANTES, and MCP-4, both at the mRNA and pro-* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed: Dept. of Immunology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of ...

Cytokine modulators as novel therapies for airway disease

“…There is increased expression of eotaxin, eotaxin-2, MCP-3, MCP-4 and CCR3 in the airways of asthmatic patients and this correlates with increased AHR [73,74]. Several long-molecular-weight inhibitors of CCR3, including UCB 35625, SB297006 and SB328437, are effective in inhibiting eosinophil 71s recruitment in allergen models of asthma [75,76] and drugs in this class are currently undergoing clinical trials in asthma. Although it was thought that CCR3 were restricted to eosinophils, there is some evidence for their expression on Th2 and mast cells; thus, these inhibitors may have a more widespread effect than on eosinophils alone, making them potentially more valuable in asthma treatment.…”

Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury

“…Antichemokine strategies include antibodies, N-terminal modified chemokines, and small-molecule antagonists (7)(8)(9). Here we describe a class of GPCR inhibitors that specifically block the inflammatory CXCL8 chemokine receptors CXCR1 and CXCR2 by means of an allosteric noncompetitive mode of interaction and protection against RI.…”

Selective suppression of leukocyte recruitment in allergic inflammation

“…An alternative is to inhibit eosinophil recruitment into tissue, where the Eotaxins are thought to play a major part, acting via CCR3. Several low molecular weight CCR3 receptor antagonists have been developed that can effectively block eosinophil migration (White et al 2000, Sabroe et al 2000, Naya et al 2001, Varnes et al 2004). Some of these compounds have reached the early stages of clinical trials.…”