Novel Derivative of Bardoxolone Methyl Improves Safety for the Treatment of Diabetic Nephropathy
Novel Derivative of Bardoxolone Methyl Improves Safety for the Treatment of Diabetic Nephropathy
复制标题
甲基巴多索隆的新型衍生物提高了治疗糖尿病肾病的安全性
DOI：
10.1021/acs.jmedchem.7b00971
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发表时间：
2017-11-09
影响因子：
7.3
通讯作者：
Zhang, Yihua
中科院分区：
文献类型：
--
作者：
Huang, Zhangjian;Mou, Yi;Zhang, Yihua
Currently, no effective and safe medicines are available to treat diabetic nephropathy (DN). Bardoxolone methyl (CDDO-Me) has displayed promising anti-DN activity as well as serious side effects in clinical trials, probably because the highly reactive alpha-cyano-alpha,beta-unsaturated ketone (CUR) in ring A of CDDO-Me can covalently bind to thiol functionalities in many biomacromolecules. In this study, we designed and synthesized,a gamma-glutamyl transpeptidase (GGT)-based and CUK-modified derivative of CDDO-Me (2) to address this issue. 2 can be specifically cleaved by GGT, which is highly expressed in the kidney, to liberate CDDO-Me in situ. It should be noted that 2 exhibited anti-DN efficacy comparable to that of CDDO-Me with much less toxicity in cells and db/db mice, suggesting that its safety is better than CDDO-Me. Our findings not only reveal the therapeutic potential of 2 but also provide a strategy to optimize other synthetic molecules or natural products bearing a pharmacophore like CUK to achieve safer pharmaceutical drugs.
