1. Academic Validation
  2. Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor

Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor

  • Eur J Med Chem. 2019 Feb 1;163:864-882. doi: 10.1016/j.ejmech.2018.12.028.
Yali Li 1 Taomin Huang 2 Bin Lou 3 Deyong Ye 3 Xiangyu Qi 3 Xiaoxia Li 3 Shuang Hu 3 Tingbo Ding 3 Yan Chen 3 Yang Cao 3 Mingguang Mo 3 Jibin Dong 3 Min Wei 3 Yong Chu 3 Huiti Li 3 Xian-Cheng Jiang 4 Nengneng Cheng 5 Lu Zhou 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China; Institute for Agro-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, No.1000, Jinqi Rd., Shanghai, 201403, China.
  • 2 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China; Eye Ear Nose Throat Hospital, Fudan University, No. 83, Fenyang Rd., Shanghai, 200031, China.
  • 3 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China.
  • 4 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China; State University of New York Downstate Medical Center, Brooklyn, NY, 11203, USA. Electronic address: xjiang@downstate.edu.
  • 5 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China. Electronic address: chengnn@163.com.
  • 6 School of Pharmacy, Fudan University, No.826, Zhangheng Rd, Shanghai, 201203, China. Electronic address: zhoulu@fudan.edu.cn.
Abstract

The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased Cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.

Keywords

ApoE KO mice; Atherosclerosis; Inhibitor; Sphingomyelin synthase 2.

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