title: Effects of the new ethacrynic acid derivative SA9000 on intraocular pressure in cats and monkeys.
abstract: To evaluate the pharmacological characteristics of the new ethacrynic acid (ECA) derivative SA9000, we examined its ocular hypotensive effects in cats and cynomolgus monkeys, its corneal toxicity in rabbits, and its binding affinities for forty-three receptors, ion channels, and second messenger systems. A 20 microl injection into the anterior chamber of eye (intracameral injection) of 0.1 mM SA9000 significantly reduced intraocular pressure (IOP) 3.8 mmHg in cats. A 10 microl intracameral injection of 1 mM SA9000 significantly reduced IOP 7 mmHg in living monkeys without evidence of in vivo (or in vitro) toxicity. The ocular hypotensive effect of SA9000 in monkeys was greater than that of ECA. The morphology of corneal endothelial and epithelial cells in rabbit eyes after intracameral injection of SA9000 was observed using electron microphotography. SA9000 at 2 mM did not induce any abnormalities, indicating that it has no corneal toxicity at a concentration higher than the minimum needed for an ocular hypotensive effect (1 mM). SA9000 at 0.01 mM showed negligible binding affinity for, or inhibition of, forty-three different receptors, ion channel proteins, and second messenger systems. These findings indicate that SA9000 has the potential to be both effective and safe as an ocular hypotensive drug, although the mechanism of action remains unclear.
authors.affiliation: Research and Development Center, Santen Pharmaceutical Co. Ltd., Ikoma, Japan. atsushi.shimazaki@santen.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Ponugoti Vasantha
authors.initials: PV
authors.lastname: Rao
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kirihara
authors.forename: Kouji
authors.initials: K
authors.lastname: Konomi
authors.forename: David Lee
authors.initials: DL
authors.lastname: Epstein
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D002415:Cats; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D003315:Cornea / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004976:Ethacrynic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D008252:Macaca fascicularis; D011817:Rabbits
chemical_list: D002934:Cinnamates; D004232:Diuretics; C496163:SA9000; D004976:Ethacrynic Acid