CCR3 Small Molecule Antagonists

UCB 35625 (16), which has already been described as having CCRl activity, also functions as a CCR3 antagonist. This compound inhibits a chemotactic response to transfected cells expressing either CCRl or CCR3 (CCRl/ MlP-la IC50 = 9.6 nAf, CCR3/eotaxin IC50 = 93.7 nAf) (89). Again, this dual activity is not surprising, given the considerable homology between the two receptors. Because (16) is not as effective in ligand displacement binding assay as it is in blocking receptor function, this suggests that it may bind with a common region in both CCRl and CCR3 that are necessary for initiation of receptor signaling.

Another tool for measuring cellular response is a shape-change assay, as measured by gated autofluorescence/forward scatter (GAFS) through flow cytometry (154, 155). Eosinophil shape change in response to eotaxin was effectively blocked by (16) (89).

In an effort to improve CCR3-selective antagonists, carboxamide derivatives based on (16) were synthesized (156). Given that it was presumed that the ammonium salt was forming an important electrostatic interaction with a carboxylate in the receptor, an amine moiety was maintained within the template. The 2-0benzothiazolethio)acetamide (29) showed po-

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