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-1 beta, IL-17, and TNF-alpha and MMP2 in cornea and conjunctiva of DED mice.

Automated summary

Dry eye disease (DED) is a common ocular disease with limited treatment options. CFTR, a major chloride channel, may provide new therapeutic strategies for DED. This study optimized a CFTR activator, 16d, with suitable solubility for eye drop formulation. Topical instillation of 16d significantly enhanced tear secretion, improved corneal erosion, and reduced pro-inflammatory cytokines in DED mice.