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 language||English (US)|
|Number of pages||11|
|Journal||Journal of medicinal chemistry|
|State||Published - Jul 14 2016|
Bibliographical noteFunding Information:
Research reported in this publication was supported by the National Eye Institute (Grant EY21727; M.P.F.), Research to Prevent Blindness (M.P.F.), Mayo Foundation (M.P.F.), and the Minnesota Partnership for Biotechnology (MNP no. 12.06 and TPDF no. 15.01; P.I.D. and M.P.F.) and the National Center for Advancing Translational Sciences of the National Institutes of Health, Award Number UL1TR000114 (P.I.D.).
© 2016 American Chemical Society.
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