A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma

• Published in: Journal of ocular pharmacology and therapeutics Vol. 26; no. 2; p. 125
• Main Authors: Borghi, Valentina, Bastia, Elena, Guzzetta, Massimiliano, Chiroli, Valerio, Toris, Carol B, Batugo, Minerva R, Carreiro, Samantha T, Chong, Wesley K M, Gale, David C, Kucera, David J, Jia, Liu, Prasanna, Ganesh, Ongini, Ennio, Krauss, Achim H P, Impagnatiello, Francesco
• Format: Journal Article
• Language: English
• Published: United States 01.04.2010
• Subjects: Animals; Antihypertensive Agents - pharmacology; Aqueous Humor - metabolism; Ciliary Body - metabolism; Cyclic GMP - metabolism; Disease Models, Animal; Dogs; Female; Glaucoma - drug therapy; Glaucoma - metabolism; Intraocular Pressure - drug effects; Iris - metabolism; Macaca fascicularis; Macrophages - drug effects; Macrophages - metabolism; Male; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Ocular Hypertension - drug therapy; Ocular Hypertension - metabolism; Ophthalmic Solutions - pharmacology; Prostaglandins F, Synthetic - chemical synthesis; Prostaglandins F, Synthetic - pharmacology; Prostaglandins, Synthetic - pharmacology; Rabbits; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism
• ISSN: 1557-7732
• DOI: 10.1089/jop.2009.0120

Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.