A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs

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 bima...

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Bibliographic Details
Published in:	Experimental eye research Vol. 93; no. 3; pp. 243 - 249
Main Authors:	Impagnatiello, F., Borghi, V., Gale, D.C., Batugo, M., Guzzetta, M., Brambilla, S., Carreiro, S.T., Chong, W.K.M., Prasanna, G., Chiroli, V., Ongini, E., Krauss, A.H.P.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-09-2011
Subjects:	Amides - pharmacology Animals Antihypertensive Agents - chemistry Antihypertensive Agents - pharmacology Aorta - drug effects Bimatoprost Chromatography, High Pressure Liquid Cloprostenol - analogs & derivatives Cloprostenol - pharmacology Dinoprost - metabolism Disease Models, Animal Dogs glaucoma Glaucoma - drug therapy Glaucoma - metabolism Intraocular Pressure - drug effects Male Molsidomine - pharmacology NCX 139 Nitrates - chemistry Nitrates - pharmacology nitric oxide Nitric Oxide - metabolism Nitric Oxide Donors - chemistry Nitric Oxide Donors - pharmacology ocular hypertension Ocular Hypertension - drug therapy Ocular Hypertension - metabolism Prostaglandins F, Synthetic - chemistry Prostaglandins F, Synthetic - metabolism Prostaglandins F, Synthetic - pharmacology Rabbits Tandem Mass Spectrometry Tonometry, Ocular Vasodilation - physiology Vasodilator Agents - pharmacology NO nitric oxide ocular hypertension Molsidomine glaucoma NCX 139 cGMP IOP FP receptor BAK ODQ sGC
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Summary:	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 3H-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. ► NCX 139 is a new chemical entity comprising latanoprost amide and a NO-donating moiety. ► NCX 139 but not its des-nitro analog resulted in selective NO-mediated vasorelaxant effect in pre-contracted rabbit aortic rings and 3H-PGF2α binding activity. ► NCX 139 significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ max = −12.8 ± 2.0 mmHg) in transiently ocular hypertensive rabbits. ► In normotensive and glaucomatous dogs, NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro analog. ► Data support the concept that NCX 139 by targeting two different mechanisms, exerts potent ocular hypotensive effects in two different animal species.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-4835 1096-0007
DOI:	10.1016/j.exer.2011.02.006