The Institute of Vision Research, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemungu, Seoul 03722, Korea.
Research Laboratories, ILDONG Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea.
J Med Chem. 2023 Jan 12;66(1):413-434. doi: 10.1021/acs.jmedchem.2c01382. Epub 2022 Dec 26.
Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to , a potent CFTR activator with suitable solubility for eye drop formulation. Notably, was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1β, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.
干眼症（DED）是最常见的眼部疾病之一，但治疗选择有限。囊性纤维化跨膜电导调节因子（CFTR）是一种主要的氯离子通道，可刺激眼表的液体分泌，可能为 DED 的新治疗策略铺平道路。在此，我们报告了 Cact-3 的优化，Cact-3 是一种有效的 CFTR 激活剂，但溶解度较差，优化为 ，一种具有合适溶解度的有效 CFTR 激活剂，可用于滴眼剂配方。值得注意的是，在兔体内， 分布于包括角膜和结膜在内的靶组织中，全身暴露最小。局部眼部滴注 可显著增加 DED 小鼠的泪液分泌，并改善角膜侵蚀。此外， 在 DED 小鼠的角膜和结膜中，显著降低了促炎细胞因子（包括 IL-1β、IL-17 和 TNF-α）和 MMP2 的 mRNA 表达。
