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Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
- Source :
- European Journal of Medicinal Chemistry. 163:864-882
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Chemokine
Apolipoprotein B
medicine.medical_treatment
Transferases (Other Substituted Phosphate Groups)
Pharmacology
01 natural sciences
Cell Line
Mice
03 medical and health sciences
Apolipoproteins E
Pharmacokinetics
Drug Discovery
medicine
Animals
Homeostasis
Humans
Macrophage
Secretion
030304 developmental biology
Inflammation
Mice, Knockout
0303 health sciences
biology
010405 organic chemistry
Chemistry
Macrophages
Organic Chemistry
General Medicine
Atherosclerosis
Lipid Metabolism
0104 chemical sciences
Cytokine
Benzamides
Knockout mouse
biology.protein
Efflux
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 163
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....65229101f6fb5a13f083685e2d75e327