Characterization of CCX140-B, an orally bioavailable antagonist of the CCR2 chemokine receptor, for the treatment of type 2 diabetes and associated complications

The chemokine receptor CCR2 is central for migration of certain populations of monocytes and T cells into sites of inflammation. We report the discovery of a novel small molecule, CCX140-B, that is an orally bioavailable, selective and potent antagonist of human CCR2. CCX140-B inhibited CCR2-mediated Ca2+ mobilization and chemotaxis in THP-1 cells with IC50 values of 10 and 3.3 nM, respectively. CCX140-B inhibited chemotaxis of primary CCR2-expressing human monocytes towards CCL2 (MCP-1) with an IC50 of 8 nM. Human CCR2 knock-in mice were used to assess the in vivo effects of CCX140-B, which does not interact with mouse CCR2. Treatment of these mice with CCX140-B resulted in reduced recruitment of peripheral monocytes in a sterile peritonitis model and normalization of insulin resistance in diet induced obese (DIO) transgenic mice. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma CCL2 levels or blood monocyte numbers in mice. In two Phase 1 clinical trials, CCX140-B was administered to healthy human volunteers and found to be well tolerated and to have a linear pharmacokinetic profile with a T1/2 of 48- 60 hours. Similar to the findings in mice, there were no effects on plasma CCL2 levels or blood monocyte numbers. This study identifies the doses required to effectively block CCR2 on blood monocytes and has informed the doses selected in various ongoing Phase 2 clinical trials.