CCX140 is a potent CCR2 antagonist. CCX140-B potently inhibits CCL2-induced chemotaxis of purified human blood monocytes with IC50 values of 8 nM in buffer and 200 nM in the presence of 100% human serum. CCX140-B also inhibits CCL2-induced Ca2+ mobilization in monocytes with an IC50 value of 3 nM. CCX140-B inhibits the binding of 125I-CCL2 to monocytes with an IC50 value of 17 nM. CCX140-B has a Kd value of 2.3 nM toward hCCR2. CCX140-B also inhibits monocyte chemotaxis mediated by the other CCR2 ligands: CCL8/MCP-2, CCL7/MCP-3, and CCL13/MCP-4. Treatment of hCCR2 KI mice with CCX140-B causes a dose-dependent reduction in the number of peritoneal leukocytes after thioglycollate challenge: CCX140-B strongly blocks leukocyte infiltration at 30 mg/kg, partially blocks leukocyte infiltration at 10 mg/kg, and fails to block leukocyte infiltration at 3 mg/kg. In DIO hCCR2 KI mice, treatment with 100 mg/kg CCX140-B blocks the progressive increase in UAER and ACR. CCX140-B maintains lower UAER and ACR values during the entire 8-wk dosing regimen. In DIO mice, the CCR2 antagonist completely blocks the recruitment of inflammatory macrophages to visceral adipose tissue. The mice exhibit reduced hyperglycemia and insulinemia, improved insulin sensitivity, increased circulating adiponectin levels, decreased pancreatic islet size and increased islet number. It also reduces urine output, glucose excretion, hepatic glycogen and triglyceride content and glucose 6-phosphatase levels.