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Abstract #45630 Published in IGR 13-2
A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs
Impagnatiello F; Borghi V; Gale DC; Batugo M; Guzzetta M; Brambilla S; Carreiro ST; Chong WKM; Prasanna G; Chiroli VExperimental Eye Research 2011;
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((registered trademark))) and the prostaglandin agonist, latanoprost (Xalatan((registered trademark))) 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 (plus or minus) 0.06 (mu)M; E( max) = 80.6 (plus or minus) 2.9%). Like bimatoprost (IC(50) = 3.07 (plus or minus) 1.3 (mu)M) or latanoprost (IC(50) = 0.48 (plus or minus) 0.15 (mu)M), NCX 139 displaced (3)H-PGF2(alpha) binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77 (plus or minus) 0.13 (mu)M. 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, (Delta)(max) = -12.8 (plus or minus) 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 ((Delta)(max) = -4.6 (plus or minus) 1.0 and -2.7 (plus or minus) 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.
F. Impagnatiello. NicOx Research Institute, Via L. Ariosto 21, 20091 Bresso, Milan, Italy, . Email: impagnatiello@nicox.it
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
11.4 Prostaglandins (Part of: 11 Medical treatment)
5.3 Other (Part of: 5 Experimental glaucoma; animal models)