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Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4506-4513. doi: 10.1167/iovs.17-22525.

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

Author information

1
Departments of Medicine and Physiology, University of California, San Francisco, California, United States.
2
Department of Ophthalmology, Palo Alto Medical Foundation, Palo Alto, California, United States.

Abstract

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 CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-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 CFTRact-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 CFTRact-K267. A single topical dose of 3 nmol CFTRact-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, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.

Conclusions:

These studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders.

PMID:
28873176
PMCID:
PMC5584707
DOI:
10.1167/iovs.17-22525
[Indexed for MEDLINE]
Free PMC Article

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