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

作者：Chowdhury Uttio Roy; Viker Kimberly B; Stolz Kristen L; Holman Bradley H; Fautsch Michael P; Dosa Peter I

来源：Journal of Medicinal Chemistry, 2016, 59(13): 6221-6231.

DOI：10.1021/acs.jmedchem.6b00406

ATP-sensitive potassium (K-ATP) channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure (TOP) in animal models and cultured human anterior segments. We have prepared water-soluble phosphate and dipeptide derivatives of the K-ATP channel opener cromakalim and evaluated their TOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering TOP 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.

• 出版日期2016-7-14