A novel C-C chemokine receptor 2 antagonist prevents progression of albuminuria and atherosclerosis in mouse models

Abstract

C-C chemokine ligand 2 (CCL2)/its receptor (CCR2) axis is considered as an important signaling pathway in inflammatory diseases. TLK-19705 is a novel CCR2 antagonist, (1-(1,3-dimethyl-1-H-pyrazolo[3,4-b]-pyridine-5-carbonyl)-3-(4- fluoro-3-(trifluoromethyl)phenyl)urea), and the inhibitory activity was antagonized by the third extracellular loop peptide of CCR2. We examined in this study the effects of TLK-19705 on diabetic nephropathy and atherosclerosis in mouse models. Treatment with TLK-19705 (30mg/kg/d) for 8 weeks ameliorated urinary albumin-creatinine ratio in db/db mice. In addition, TLK-19705, given at 10 mg/kg/d for 8 weeks, significantly reduced the areas of atherosclerotic lesion in apolipoprotein E knockout mice. In conclusion, the results of this study indicate not only considerable therapeutic potential of CCR2 antagonists for diabetic nephropathy and atherosclerosis, but also that TLK-19705 would serve as a powerful tool in mechanistic investigation of these inflammatory diseases. © 2012 The Pharmaceutical Society of Japan.