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

[Display omitted] 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...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2018-01, Vol.28 (2), p.222-229
Hauptverfasser: Chen, Jun, Peng, Zhangzhe, Lu, Miaomiao, Xiong, Xuan, Chen, Zhuo, Li, Qianbin, Cheng, Zeneng, Jiang, Dejian, Tao, Lijian, Hu, Gaoyun
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Sprache:eng
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Zusammenfassung:[Display omitted] 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 90μM in NIH3T3 cell lines, t1/2 of 4.89±1.33h in male rats and LD50>2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.07.001