Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide–donating bimatoprost in preclinical models

Francesco Impagnatiello, Carol B Toris, Minerva Batugo, Ganesh Prasanna, Valentina Borghi, Elena Bastia, Ennio Ongini, Achim H P Krauss

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose. 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 lL) lowered IOP in tOHT-rabbits with an Emax of ±7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, ±5.4 6 0.7 and ±3.4 6 0.7 mm Hg, respectively, P <0.05) and in OHT-monkeys (IOP change, ±7.7 6 1.4 and ±4.8 6 1.7 mm Hg, respectively, P <0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) 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.

Original languageEnglish (US)
Pages (from-to)6558-6564
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number11
DOIs
StatePublished - 2015

Fingerprint

Intraocular Pressure
Ciliary Body
Aqueous Humor
Iris
Rabbits
Haplorhini
Dinoprost
Cornea
Nitric Oxide
Bimatoprost
Dogs
Synthetic Prostaglandins
Trabecular Meshwork
Ocular Hypertension
Acids
Macaca fascicularis
Immunoenzyme Techniques
Liquid Chromatography
Glaucoma
Mass Spectrometry

Keywords

  • Bimatoprost
  • Glaucoma
  • Nitric oxide
  • Ocular hypertension
  • Prostaglandin

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide–donating bimatoprost in preclinical models. / Impagnatiello, Francesco; Toris, Carol B; Batugo, Minerva; Prasanna, Ganesh; Borghi, Valentina; Bastia, Elena; Ongini, Ennio; Krauss, Achim H P.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 11, 2015, p. 6558-6564.

Research output: Contribution to journalArticle

Impagnatiello, Francesco ; Toris, Carol B ; Batugo, Minerva ; Prasanna, Ganesh ; Borghi, Valentina ; Bastia, Elena ; Ongini, Ennio ; Krauss, Achim H P. / Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide–donating bimatoprost in preclinical models. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 11. pp. 6558-6564.
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abstract = "Purpose. 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 lL) lowered IOP in tOHT-rabbits with an Emax of ±7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1{\%}, 30 lL) was noneffective in this model. NCX 470 (0.042{\%}, 30 lL) was more effective than equimolar (0.03{\%}, 30 lL) bimatoprost in ONT-dogs (IOP change, ±5.4 6 0.7 and ±3.4 6 0.7 mm Hg, respectively, P <0.05) and in OHT-monkeys (IOP change, ±7.7 6 1.4 and ±4.8 6 1.7 mm Hg, respectively, P <0.05) at 18 hours post dosing. NCX 470 (0.042{\%}, 30 lL) or bimatoprost (0.03{\%}, 30 lL) 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.",
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author = "Francesco Impagnatiello and Toris, {Carol B} and Minerva Batugo and Ganesh Prasanna and Valentina Borghi and Elena Bastia and Ennio Ongini and Krauss, {Achim H P}",
year = "2015",
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language = "English (US)",
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pages = "6558--6564",
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issn = "0146-0404",
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TY - JOUR

T1 - Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide–donating bimatoprost in preclinical models

AU - Impagnatiello, Francesco

AU - Toris, Carol B

AU - Batugo, Minerva

AU - Prasanna, Ganesh

AU - Borghi, Valentina

AU - Bastia, Elena

AU - Ongini, Ennio

AU - Krauss, Achim H P

PY - 2015

Y1 - 2015

N2 - Purpose. 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 lL) lowered IOP in tOHT-rabbits with an Emax of ±7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, ±5.4 6 0.7 and ±3.4 6 0.7 mm Hg, respectively, P <0.05) and in OHT-monkeys (IOP change, ±7.7 6 1.4 and ±4.8 6 1.7 mm Hg, respectively, P <0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) 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.

AB - Purpose. 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 lL) lowered IOP in tOHT-rabbits with an Emax of ±7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, ±5.4 6 0.7 and ±3.4 6 0.7 mm Hg, respectively, P <0.05) and in OHT-monkeys (IOP change, ±7.7 6 1.4 and ±4.8 6 1.7 mm Hg, respectively, P <0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) 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.

KW - Bimatoprost

KW - Glaucoma

KW - Nitric oxide

KW - Ocular hypertension

KW - Prostaglandin

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U2 - 10.1167/iovs.15-17190

DO - 10.1167/iovs.15-17190

M3 - Article

VL - 56

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EP - 6564

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

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