Structure鈥揂ctivity and Structure鈥揚roperty Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1鈥揘rf2 Protein鈥揚rotein Interaction Inhibitor
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- 作者：Zheng-Yu Jiang ; Li鈭扡i Xu ; Meng-Chen Lu ; Zhi-Yun Chen ; Zhen-Wei Yuan ; Xiao-Li Xu ; Xiao-Ke Guo ; Xiao-Jin Zhang ; Hao-Peng Sun ; Qi-Dong You
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 27, 2015
- 年：2015
- 卷：58
- 期：16
- 页码：6410-6421
- 全文大小：532K
- ISSN：1520-4804
文摘
Directly disrupting the Keap1鈥揘rf2 protein鈥損rotein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1鈥揘rf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure鈥揳ctivity and structure鈥損roperty relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1鈥揘rf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.