Treatment of hCCR2 KI mice with CCX140 (CCX140-B) causes a dose-dependent reduction in the number of peritoneal leukocytes after thioglycollate challenge: CCX140 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 blocks the progressive increase in UAER and ACR. CCX140 maintains lower UAER and ACR values during the entire 8-wk dosing regimen[1]. 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. CCX140 also reduces urine output, glucose excretion, hepatic glycogen and triglyceride content and glucose 6-phosphatase levels[2].
