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

Jintong YANG; Yiteng LU; Kexin HU; Xinchen ZHANG; Wei WANG; Deyong YE; Mingguang MO; Xin XIAO; Xichen WAN; Yuqing WU; Shuxian ZHANG; He HUANG; Zhibei QU; Yimin HU; Yu CAO; Jiaxu HONG; Lu ZHOU

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

Author: Jintong YANG ¹ ; Yiteng LU ² ; Kexin HU ³ ; Xinchen ZHANG ¹ ; Wei WANG ¹ ; Deyong YE ¹ ; Mingguang MO ¹ ; Xin XIAO ¹ ; Xichen WAN ² ; Yuqing WU ² ; Shuxian ZHANG ⁴ ; He HUANG ⁴ ; Zhibei QU ¹ ; Yimin HU ¹ ; Yu CAO ³ ; Jiaxu HONG ² ; Lu ZHOU ¹
Author Information

1. School of Pharmacy, Fudan University, Shanghai 201203, China.
2. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200031, China.
3. Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
4. Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
Publication Type:Journal Article
Keywords: Dry eye disease; Human corneal epithelial cells; Meibomian glands; SMS2 inhibitor; Sphingomyelin; Sphingomyelin synthase 2; Thiophene carboxamide; Tumor necrosis factor receptor 1
From: Acta Pharmaceutica Sinica B 2025;15(1):392-408
CountryChina
Language:English
Abstract: 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 (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-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-α, Il-1β 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.