Tyrosine analog SK&F 45523 23, was identified in a FLIPR-based screen measuring effects on eotaxin-induced Ca2+ flux in RBL-2H2 cells transfected with human CCR3 (67). Compound 23 inhibited binding of 125l eotaxin to human eosinophils with an IC5o = 800 nM. Elaboration of the design led to SB-328437 24 which is a potent antagonist in the eosinophil binding assay (IC50 = 4.5 nM), and is a functional CCR3 antagonist since it inhibits eotaxin-induced Ca2+ flux in human eosinophils (IC5o = 35 nM) (68). Moreover, compound 24 is at least 250-fold selective over a panel of other chemokine receptors. More recent patent applications claim compounds where the ester group of 24 is replaced by less metabolically labile dihydrooxazole amide and hydrazino groups (69-71).
Conclusion - There is strong evidence linking eosinophil recruitment and activation in the lung with bronchial asthma and allergic rhinitis. More recently, the chemokine receptor CCR3 has been identified as a potentially critical receptor in respiratory migration of eosinophils (5,6). Since then, significant progress has been made to identify potent, small molecule antagonists of CCR3. Interestingly, most CCR3 antagonist designs possess a basic nitrogen. This phenomenon is also found in many compounds which bind to other receptors in the chemokine family. Based on mutagenesis studies of CCR2 and CCR5, it was postulated that the basic nitrogen present in these designs interacts with a glutamic acid in transmembrane helix 7 (72, 73). This amino acid is present in CCR3 in this region as well. In the new era of targeted therapy for respiratory diseases, it remains to be determined in anticipated clinical studies whether CCR3 antagonists will fulfill their therapeutic potential.
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