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

Jun Chen; Zhangzhe Peng; Miaomiao Lu; Xuan Xiong; Zhuo Chen; Qianbin Li; Zeneng Cheng; Dejian Jiang; Lijian Tao; Gaoyun Hu

doi:10.1016/j.bmcl.2017.07.001

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

Bioorg Med Chem Lett. 2018 Jan 15;28(2):222-229. doi: 10.1016/j.bmcl.2017.07.001. Epub 2017 Jul 4.

Authors

Jun Chen¹, Zhangzhe Peng², Miaomiao Lu², Xuan Xiong², Zhuo Chen¹, Qianbin Li¹, Zeneng Cheng¹, Dejian Jiang³, Lijian Tao², Gaoyun Hu⁴

Affiliations

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.
⁴ Department of Medicinal Chemistry, Xiangya School of Pharmacy, Central South University, Changsha 410013, China. Electronic address: [email protected].

PMID: 29248299
DOI: 10.1016/j.bmcl.2017.07.001

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 90μM in NIH3T3 cell lines, t_1/2 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.

Keywords: Anti-Diabetic Nephropathy; Anti-fibrosis; Anti-inflammatory; Multi-target; Pyridone derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / pathology
Diabetic Nephropathies / drug therapy*
Diabetic Nephropathies / pathology
Dose-Response Relationship, Drug
Drug Discovery*
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Kidney Failure, Chronic / drug therapy*
Kidney Failure, Chronic / pathology
Male
Mice
Molecular Structure
NIH 3T3 Cells
Oxidative Stress / drug effects
Piperazines / administration & dosage
Piperazines / chemistry
Piperazines / pharmacology*
Pyridones / administration & dosage
Pyridones / chemistry
Pyridones / pharmacology*
Rats
Structure-Activity Relationship

Substances

1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one
Anti-Inflammatory Agents, Non-Steroidal
Hypoglycemic Agents
Piperazines
Pyridones