Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR (cystic fibrosis transmembrane conductance regulator) is a major pro-secretory chloride channel at the ocular surface. Using high-throughput screening platform, we previously identified aminophenyl-1,3,5-triazine CFTRact-K089 that activated CFTR with EC50 ~250 nM. When delivered topically CFTRact-K089 increased tear fluid secretion in mice and showed efficacy in an experimental dry eye model. Based on preliminary SAR data from commercially available aminophenyl-1,3,5-triazine analogs, we synthesized novel analogs and conducted functional studies. The most potent analog fully activated CFTR chloride conductance with EC50 ~30 nM, without causing cAMP or calcium signaling. The potent triazine analog was non-toxic, stable in an ophthalmic vehicle, and rapid metabolized by hepatic microsomes, which supports its topical use in dry eye disease. In vivo studies showed increased tear volume for 8 h in wild type mice following a single topical administration, and no effect in CFTR-deficient mice. In summary, we designed and synthesized aminophenyl-1,3,5-triazine CFTR activators, which are novel candidates for treatment of dry eye disease.

Nanomolar-potency aminophenyl-1,3,5-triazine CFTR chloride channel activators for pro-secretory therapy of dry eye diseases

253rd National Meeting (2017)

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