title: 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.
abstract: 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.
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Sujin
authors.identifier: 0000-0003-3345-2073
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Felix
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Joseph-Anthony
authors.initials: JA
authors.lastname: Tan
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Levin
authors.affiliation: Departments of Medicine and Physiology, University of California , San Francisco, California 94143-0521, United States.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D015352:Dry Eye Syndromes / Q000188:drug therapy*; D006801:Humans; D036103:Nanotechnology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000494:pharmacology*
chemical_list: D014227:Triazines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator