14-17 Septembre 2011
35° Congresso Nazionale della Società Italiana di Farmacologia .
Ocular hypotensive effects of NCX 139, a nitric oxide (NO)-donating latanoprost amide, in normotensive and ocular hypertensive rabbits and dogs
F. Impagnatiello1, V. Borghi1, F. Benedini1, S.T. Carreiro2, W.K.M. Chong2, G. Prasanna2, A.H.P. Krauss2 and E. Ongini1
1NicOx Research Institute, Bresso, Milan, Italy
2Pfizer Global Research & Development-La Jolla, San Diego, USA
Nitric oxide (NO) signaling regulates intraocular pressure (IOP) and regional eye blood flow with mechanisms complementary to those of prostamides and prostaglandins. NCX 139 is a novel compound comprising latanoprost amide and a NO-donating moiety which we recently synthesized to achieve greater IOP lowering and improved ocular perfusion compared to currently approved medications in glaucoma therapy.
NCX 139 was synthesized in house and later characterized with respect to its NO and prostaglandin-F (FP) binding properties. We also determined the IOP-lowering effects of this drug in rabbit and dog models of hypertensive glaucoma. The respective des-nitro analog as well as the prostamide, bimatoprost and the prostaglandin, latanoprost, were included for comparison.
NCX 139 but not its des-nitro analog resulted in selective NO-mediated vascular relaxant effect (EC50 = 0.70 ±0.06 microM; Emax= 80.6 ±2.9%). Like bimatoprost (IC50=3.07 ± 1.3microM), NCX 139 displaced 3H-PGF2alpha binding to human FP receptors with an estimated potency of 0.77 ± 0.13 microM.
In transiently ocular hypertensive rabbits which are not responsive to prostaglandin and prostamide mimetics, NCX 139 significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Deltamax= -12.8 ±2.0 mmHg) suggesting a direct contribution of NO in this model. In glaucomatous dogs, NCX 139 decreased the IOP to greater extent compared to the des-nitro analog (Deltamax= -4.6 ±1.0 and -2.7 ±1.3 mmHg for NCX 139 and its des-nitro analog, respectively). In this model, both bimatoprost and latanoprost also resulted effective.
The data suggest that NCX 139 has potent ocular hypotensive activity in the rabbit and dog elevated IOP models. These effects are likely dependent on two mechanisms involving NO and FP signalling.