Analogs of the ATP-Sensitive Potassium (KATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Uttio Roy Chowdhury, Kimberly B. Viker, Kristen L. Stoltz, Bradley H. Holman, Michael P. Fautsch, Peter I. Dosa

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

ATP-sensitive potassium (KATP) channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure (IOP) in animal models and cultured human anterior segments. We have prepared water-soluble phosphate and dipeptide derivatives of the KATP channel opener cromakalim and evaluated their IOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering IOP with once daily dosing in a normotensive mouse model. Two of these phosphate derivatives were further evaluated in a normotensive rabbit model, with a significant difference in activity observed. No toxic effects on cell structure or alterations in morphology of the aqueous humor outflow pathway were observed after treatment with the most efficacious compound, (3S,4R)-2, suggesting that it is a strong candidate for development as an ocular hypotensive agent.

Original languageEnglish (US)
Pages (from-to)6221-6231
Number of pages11
JournalJournal of Medicinal Chemistry
Volume59
Issue number13
DOIs
StatePublished - Jul 14 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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