Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye Diseases

Dry eye disorders
are a significant health problem for which limited
therapeutic options are available. CFTR is a major prosecretory chloride
channel at the ocular surface. We previously identified, by high-throughput
screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ≈ 250 nM,
which when delivered topically increased tear fluid secretion in mice
and showed efficacy in an experimental dry eye model. Here, functional
analysis of aminophenyl-1,3,5-triazine analogs elucidated structure–activity
relationships for CFTR activation and identified substantially more
potent analogs than 1. The most potent compound, 12, fully activated CFTR chloride conductance with EC50 ≈ 30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports
its topical use. Single topical administration of 25 pmol of 12 increased tear volume in wild-type mice with sustained
action for 8 h and was without effect in CFTR-deficient mice. Topically
delivered 12 may be efficacious in human dry eye diseases.