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

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Valentina Borghi, Elena Bastia, Massimiliano Guzzetta, Valerio Chiroli, Carol B Toris, Minerva R Batugo, Samantha T Carreiro, Wesley K M Chong, David C Gale, David J Kucera, Liu Jia, Ganesh Prasanna, Ennio Ongini, Achim H P Krauss, Francesco Impagnatiello
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 26 Issue 2 Pg. 125-32 (Apr 2010) ISSN: 1557-7732 [Electronic] United States
• PMID: 20415621 (Publication Type: Journal Article)

Chemical References

• 1-(nitrooxymethyl)-2-(nitrooxy)ethyl 7-(3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl)-5-heptenoate
• Antihypertensive Agents
• Ophthalmic Solutions
• Prostaglandins F, Synthetic
• Prostaglandins, Synthetic
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Cyclic GMP

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Aqueous Humor (metabolism)
• Ciliary Body (metabolism)
• Cyclic GMP (metabolism)
• Disease Models, Animal
• Dogs
• Female
• Glaucoma (drug therapy, metabolism)
• Intraocular Pressure (drug effects)
• Iris (metabolism)
• Macaca fascicularis
• Macrophages (drug effects, metabolism)
• Male
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Ocular Hypertension (drug therapy, metabolism)
• Ophthalmic Solutions (pharmacology)
• Prostaglandins F, Synthetic (chemical synthesis, pharmacology)
• Prostaglandins, Synthetic (pharmacology)
• Rabbits
• Tumor Cells, Cultured (drug effects, metabolism)