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

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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) 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, Δmax =-10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax=-6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax =-9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax =-11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax =-16.7 ± 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.

Original languageEnglish (US)
Pages (from-to)125-131
Number of pages7
JournalJournal of Ocular Pharmacology and Therapeutics
Volume26
Issue number2
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Ophthalmology
  • Pharmacology
  • Pharmacology (medical)

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