title: Analogs of the ATP-Sensitive Potassium (KATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity.
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.
authors.affiliation: Department of Ophthalmology, Mayo Clinic , 200 1st St SW, Rochester, Minnesota 55905, United States.
authors.forename: Uttio
authors.initials: U
authors.lastname: Roy Chowdhury
authors.affiliation: Department of Ophthalmology, Mayo Clinic , 200 1st St SW, Rochester, Minnesota 55905, United States.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Viker
authors.affiliation: Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Stoltz
authors.affiliation: Department of Ophthalmology, Mayo Clinic , 200 1st St SW, Rochester, Minnesota 55905, United States.
authors.forename: Bradley H
authors.initials: BH
authors.lastname: Holman
authors.affiliation: Department of Ophthalmology, Mayo Clinic , 200 1st St SW, Rochester, Minnesota 55905, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fautsch
authors.affiliation: Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Dosa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D019806:Cromakalim / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D005123:Eye / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D054086:KATP Channels / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000959:Antihypertensive Agents; D004151:Dipeptides; D054086:KATP Channels; D010710:Phosphates; D019806:Cromakalim