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Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one,an orally active multi-target agent for the treatment of diabetic nephropathy |
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| Authors: | Jun Chen Zhangzhe Peng Miaomiao Lu Xuan Xiong Zhuo Chen Qianbin Li Zeneng Cheng Dejian Jiang Lijian Tao Gaoyun Hu |
| Institution: | 1. Department of Medicinal Chemistry, Xiangya School of Pharmacy, Central South University, Changsha 410013, China;2. Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China;3. Drug Safety Evaluation Research Center of Hunan Province, Changsha 410331, China |
| Abstract: | Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90 μM in NIH3T3 cell lines, t1/2 of 4.89 ± 1.33 h in male rats and LD50 > 2000 mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN. |
| Keywords: | ACR albumin-to-creatinine ratio area under the curve BuOH BUN blood urea nitrogen peak concentration CCr creatinine clearance rate CCR2 CCchemkin receptor 2 Deuterotrichloromethane DBM diabetes model DMF N N-dimethylformamide DMSO dimethyl sulfoxide DN diabetic nephropathy ECM extracellular matrix ELISA enzyme-linked immunosorbent assay ERSD end stage renal disease GC-MS Gas Chromatograph-Mass Spectrometer-computer GLP Good laboratory practice of drug GSI glomerular sclerosis index HMBC heteronuclear multiple bond correlation HPLC high performance liquid chromatography IR infrared radiation LC-MS liquid chromatography-mass spectrum LPS lipopolysaccharide MTT methylthiazolyl diphenyl tetrazolium bromide NIH3T3 mouse embryonic fibroblast cell line NOX nicotinamide adenine dinucleotide phosphate oxidase PD pharmacodynamics PDGF platelet-derived growth factor PFD pirfenidone PK pharmacokinetics ROS reactive oxygen species SAR structure activity relationships SCr serum creatinine TGF-β transforming growth factor-β TNF-α tumor necrosis factors-α UUO unilateral ureteral occlusion Anti-fibrosis Anti-inflammatory Anti-Diabetic Nephropathy Multi-target Pyridone derivatives |
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