Discovery of a novel thiophene carboxamide analogue as a highly potent and selective sphingomyelin synthase 2 inhibitor for dry eye disease therapy.

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 with an improved highly potent inhibitory activity on SM synthesis (IC = 28 nmol/L). Moreover, exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF--hyperosmotic stress conditions , with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (  = 1.11 h;  = 4.32 h) in rats. Furthermore, alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, reduced the mRNA expression of , and 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.