title: 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 (30 mg/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.
authors.affiliation: Mie Research Park, Sanwa Kagaku Kenkyusho Co., Ltd., Mie 511–0406, Japan. ma_okamoto@mb6.skk-net.com
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fuchigami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000652:urine; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D003404:Creatinine / Q000652:urine; D048909:Diabetes Complications / Q000188:drug therapy* / Q000652:urine; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*
chemical_list: C579426:1-(1,3-dimethyl-1-H-pyrazolo(3,4-b)pyridine-5-carbonyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea; D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D010671:Phenylurea Compounds; D011720:Pyrazoles; D054390:Receptors, CCR2; D003404:Creatinine