Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5‑a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease

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 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d 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（Dry eye disease, DED）是最常见的眼部疾病之一，但其临床治疗选择十分有限。囊性纤维化跨膜传导调节因子（Cystic fibrosis transmembrane conductance regulator, CFTR）是一类可刺激眼表液体分泌的主要氯离子通道，有望为干眼症的治疗提供全新的策略方向。本文报道了将强效CFTR激活剂Cact-3（溶解度不佳）优化为16d的研究：16d同样为强效CFTR激活剂，且其溶解度适配滴眼剂配方的要求。值得注意的是，16d在家兔体内可有效分布于角膜、结膜等靶组织，且全身暴露量极低。在干眼症小鼠模型中，眼部局部滴注16d可显著提升泪液分泌，并改善角膜糜烂症状。此外，16d可显著降低干眼症小鼠角膜与结膜组织中IL-1β、IL-17、TNF-α等促炎细胞因子以及基质金属蛋白酶2（MMP2）的mRNA表达水平。