Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,part...Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,particularly in the meibomian glands.Sphingomyelin synthase 2(SMS2),one of the proteins involved in SM synthesis,would light a novel way of developing a DED therapy strategy.Herein,we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis(IC50,SMS2 Z 28 nmol/L).Moreover,14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells(HCEC)under TNF-a-hyperosmotic stress conditions in vitro,with an acceptable ocular specific distribution(corneas and meibomian glands)and pharmacokinetics(PK)profiles(t_(1/2,cornea)= 1.11 h;t_(1/2,meibomian glands) = 4.32 h)in rats.Furthermore,14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice.Mechanically,14l reduced the mRNA expression of Tnf-a,Il-1b and Mmp-9 in corneas,as well as the proportion of very long chain SM in meibomian glands.Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.展开更多
基金supported by the National Key R&D Program of China(2023YFC3603303 and 2023YFA0915000)the National Natural Science Foundation of China(22077019 and 82171102)+3 种基金Shanghai Municipal Committee of Science and Technology(21TQ016 and 21XD1420600,China)the Shanghai Medical Innovation Research Program(22Y21900900,China)the Shanghai Key Clinical Research Program(SHDC2020CR3052B,China)the Class IV Peak Disciplines(Shanghai Institute of Precision Medicine)from the Shanghai Municipal Education Commission.The authors would like to thank Professor Weiyun Shi(Shandong Eye Hospital,Ji’nan,China).
文摘Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,particularly in the meibomian glands.Sphingomyelin synthase 2(SMS2),one of the proteins involved in SM synthesis,would light a novel way of developing a DED therapy strategy.Herein,we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis(IC50,SMS2 Z 28 nmol/L).Moreover,14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells(HCEC)under TNF-a-hyperosmotic stress conditions in vitro,with an acceptable ocular specific distribution(corneas and meibomian glands)and pharmacokinetics(PK)profiles(t_(1/2,cornea)= 1.11 h;t_(1/2,meibomian glands) = 4.32 h)in rats.Furthermore,14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice.Mechanically,14l reduced the mRNA expression of Tnf-a,Il-1b and Mmp-9 in corneas,as well as the proportion of very long chain SM in meibomian glands.Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.
