A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma.
OBJECTIVE
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.
Borghi
Valentina
V
NicOx Research Institute, Bresso, Milan, Italy.
Bastia
Elena
E
Guzzetta
Massimiliano
M
Chiroli
Valerio
V
Toris
Carol B
CB
Batugo
Minerva R
MR
Carreiro
Samantha T
ST
Chong
Wesley K M
WK
Gale
David C
DC
Kucera
David J
DJ
Jia
Liu
L
Prasanna
Ganesh
G
Ongini
Ennio
E
Krauss
Achim H P
AH
Impagnatiello
Francesco
F
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D007498:Iris / Q000378:metabolism; D008252:Macaca fascicularis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009798:Ocular Hypertension / Q000188:drug therapy / Q000378:metabolism; D009883:Ophthalmic Solutions / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000138:chemical synthesis / Q000494:pharmacology*; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D011817:Rabbits; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C551881:1-(nitrooxymethyl)-2-(nitrooxy)ethyl 7-(3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl)-5-heptenoate; D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011461:Prostaglandins F, Synthetic; D011465:Prostaglandins, Synthetic; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP