Intraocular Pressure-Lowering Activity of NCX 470, a Novel Nitric Oxide-Donating Bimatoprost in Preclinical Models.

Abstract

PURPOSE: The prostaglandin F2alpha (PGF2&#x3b1;) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. METHODS: New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. RESULTS: NCX 470 (0.14%, 30 &#x3bc;L) lowered IOP in tOHT-rabbits with an E(max) of -7.2 &#xb1; 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 &#x3bc;L) was noneffective in this model. NCX 470 (0.042%, 30 &#x3bc;L) was more effective than equimolar (0.03%, 30 &#x3bc;L) bimatoprost in ONT-dogs (IOP change, -5.4 &#xb1; 0.7 and -3.4 &#xb1; 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, -7.7 &#xb1; 1.4 and -4.8 &#xb1; 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 &#x3bc;L) or bimatoprost (0.03%, 30 &#x3bc;L) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing. CONCLUSIONS: NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2&#x3b1; and NO/cGMP signaling pathways.