Taken together, these data demonstrate that INCB3344 is a potent inhibitor of hCCR2, with IC50 values in the single digit nanomolar range for a number of assays measuring MCP-1 binding to and signaling through hCCR2. Recently, a number of novel and selective inhibitors of hCCR2 have been published [23], [24], [25], [26], [27] and [28]. The inhibitory activity of INCB3344 against hCCR2 in vitro is very similar to those of these newly described compounds. We studied the nature of INCB3344 interaction with hCCR2 and our results suggest that the JNK-IN-8 is competitive with MCP-1. This result is different from that of a study of JNJ-27141491, which was described as a noncompetitive small molecule inhibitor of hCCR2 [18], indicating that the receptor can be inhibited by different mechanisms.
We developed a FACS based CCR2 binding assay using MCP-1-Alexa-488 to measure the in vivo activity of INCB3344. While this paper was in preparation, a similar procedure was published by Wyant et al. [29] to monitor antibody neutralization of CCR2. Our data extend this method to use with small molecule antagonists.
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Distribution patterns Although both species are considered
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