Discovery of the selective sphingomyelin synthase 2 inhibitors with the novel structure of oxazolopyridine. Issue 15 (1st August 2017)

• Record Type: Journal Article
• Authors: Qi, Xiang-Yu; Cao, Yang; Li, Ya-Li; Mo, Ming-Guang; Zhou, Lu; Ye, De-Yong
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 15(2017)
• Page Start: 3511
• Page End: 3515
• Publication Date: 2017-08-01
• Subjects: SMS sphingomyelin synthase -- SM sphingomyelin -- PC phosphatidylcholine -- CHD coronary heart disease -- SMase sphingomyelinase -- SPT serine palmitoyl transferase -- AS atherosclerosis -- SMSr SMS related protein -- SAR structure-activity relationships -- IC50 half maximal inhibitory concentration -- hSMS1 human sphingomyelin synthase 1 -- hSMS2 human sphingomyelin synthase 2 -- Ile isoleucine -- Val valine -- Trp tryptophan -- Leu leucine -- Thr threonine -- Tyr tyrosine; Sphingomyelin synthase 2 -- Anti-atherosclerosis -- Oxazolopyridine -- Selective inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.074
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compoundD2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative moleculesQY4 andQY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.