title: Intraocular Pressure-Lowering Activity of NCX 470, a Novel Nitric Oxide-Donating Bimatoprost in Preclinical Models.
abstract: OBJECTIVE
  The prostaglandin F2alpha (PGF2α) 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 μL) lowered IOP in tOHT-rabbits with an E(max) of -7.2 ± 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) 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 PGF2α and NO/cGMP signaling pathways.
authors.affiliation: Nicox Research Institute Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Impagnatiello
authors.affiliation: University of Nebraska Medical Center, Omaha, Nebraska, United States.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Toris
authors.affiliation: Pfizer, Inc., San Diego, California, United States.
authors.forename: Minerva
authors.initials: M
authors.lastname: Batugo
authors.affiliation: Pfizer, Inc., San Diego, California, United States.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
authors.affiliation: Nicox Research Institute Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Borghi
authors.affiliation: Nicox Research Institute Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bastia
authors.affiliation: Nicox Research Institute Milan, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.affiliation: Pfizer, Inc., San Diego, California, United States.
authors.forename: Achim H P
authors.initials: AH
authors.lastname: Krauss
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics; D001082:Aqueous Humor / Q000378:metabolism*; D000069580:Bimatoprost / Q000493:pharmacokinetics*; D002924:Ciliary Body / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics*; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D053719:Tandem Mass Spectrometry
chemical_list: D000959:Antihypertensive Agents; D020030:Nitric Oxide Donors; D000069580:Bimatoprost