Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders

PURPOSE: Pharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTR(act)-K267), fully activated human wildtype CFTR with EC(50) ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTR(act)-K267 were done in adult New Zealand white rabbits. METHODS: CFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTR(act)-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration. RESULTS: Electrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTR(act)-K267. A single topical dose of 3 nmol CFTR(act)-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTR(act)-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs. CONCLUSIONS: These studies support the development of CFTR(act)-K267 as a pro-secretory therapy for dry eye disorders.