title: A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs.
abstract: The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 μM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 μM) or latanoprost (IC(50)=0.48±0.15 μM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.
authors.affiliation: NicOx Research Institute, Via L. Ariosto 21, 20091 Bresso, Milan, Italy. impagnatiello@nicox.it
authors.forename: F
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: V
authors.initials: V
authors.lastname: Borghi
authors.forename: D C
authors.initials: DC
authors.lastname: Gale
authors.forename: M
authors.initials: M
authors.lastname: Batugo
authors.forename: M
authors.initials: M
authors.lastname: Guzzetta
authors.forename: S
authors.initials: S
authors.lastname: Brambilla
authors.forename: S T
authors.initials: ST
authors.lastname: Carreiro
authors.forename: W K M
authors.initials: WK
authors.lastname: Chong
authors.forename: G
authors.initials: G
authors.lastname: Prasanna
authors.forename: V
authors.initials: V
authors.lastname: Chiroli
authors.forename: E
authors.initials: E
authors.lastname: Ongini
authors.forename: A H P
authors.initials: AH
authors.lastname: Krauss
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D000069580:Bimatoprost; D002851:Chromatography, High Pressure Liquid; D003008:Cloprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008297:Male; D008981:Molsidomine / Q000494:pharmacology; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D009798:Ocular Hypertension / Q000188:drug therapy / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011817:Rabbits; D053719:Tandem Mass Spectrometry; D014065:Tonometry, Ocular; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C568858:7-(3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl)-5-heptenoic acid 6-(nitrooxy)hexyl amide; D000577:Amides; D000959:Antihypertensive Agents; D009566:Nitrates; D020030:Nitric Oxide Donors; D011461:Prostaglandins F, Synthetic; D014665:Vasodilator Agents; D009569:Nitric Oxide; D003008:Cloprostenol; D000077338:Latanoprost; D015237:Dinoprost; D008981:Molsidomine; D000069580:Bimatoprost