The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, as far as now, reports about selective SMS2 inhibitors and their pharmacological activities were lacked. A study from Yali Li discovered and identified a novel SMS2 inhibitor Ly93.

In the study, firstly, the authors discovered SMS2 inhibitors through scaffold hopping and structural optimization. And among them, Ly93, the most potent compound, represented as a selective and oral active sphingomyelin synthase 2 (SMS2) inhibitor, with an IC50 of 91 nM. In addition, the selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1.

Subsequently, the authors verified the efficacy of the inhibitor both in vitro and in vivo.

In Huh7 cells, Ly93 not only dose-dependently diminished apoB secretion, 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.

Then, the pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally active.

Furthermore, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Additionally, 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.

Overall, Ly93 exhibits excellent anti-atherosclerotic activity 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.

Li Y, et al. Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor. Eur J Med Chem. 2019 Feb 1;163:864-882.