A Novel Nitric Oxide Releasing Prostaglandin Analog, NCX 125, Reduces Intraocular Pressure in Rabbit, Dog, and Primate Models of Glaucoma
A Novel Nitric Oxide Releasing Prostaglandin Analog, NCX 125, Reduces Intraocular Pressure in Rabbit, Dog, and Primate Models of Glaucoma
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DOI：
10.1089/jop.2009.0120
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发表时间：
2010-04-01
影响因子：
2.3
通讯作者：
Impagnatiello, Francesco
中科院分区：
文献类型：
--
作者：
Borghi, Valentina;Bastia, Elena;Impagnatiello, Francesco
目的：一氧化氮(NO)通过与前列腺素互补的靶向机制参与包括眼房水动力学在内的多种生理过程。方法：合成了一种新合成的化合物NCX125，该化合物由拉坦前列素酸和NO供体部分组成。方法：体外测试NCX125释放功能性活性NO的能力，并与核心拉坦前列素在兔、狗和非人灵长类动物青光眼模型中的降眼压作用进行比较。结果：NCX125能诱导PC12细胞产生cGMP(EC(50)=3.8+/-1.0mU M)，并对NO依赖的诱导型一氧化氮合酶产生抑制作用(IC(50)=55+/-11mU M)。与等摩尔拉坦前列素相比，NCX125能更大程度地降低眼压：(A)兔一过性高眼压模型(0.030%拉坦前列素无效；0.039%NCX125，Delta(Max)=-10.6+/-2.3 mm Hg)，(B)高眼压性青光眼犬(0.030%拉坦前列素，Delta(Max)=-6.7+/-1.2 mm Hg；0.039%NCX125，Delta(Max)=-9.1+/-3.1 mm Hg)和(C)激光诱导的高眼压非人类灵长类动物(0.10%拉坦前列素，Delta(Max)=-11.9+/-3.7 mm Hg，0.13%NCX125，Delta(Max)=-16.7+/-2.2 mm Hg)。在药代动力学研究中，NCX 125和拉坦前列素在前段眼组织中引起相似的拉坦前列素游离酸暴露。结论：NCX 125是一种针对两种不同机制的化合物，具有较强的降压作用。这可能会为青光眼高危患者的治疗带来潜在的新视角。
Purpose: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties.Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma.Results: NCX 125 elicited cGMP formation (EC(50) = 3.8 +/- 1.0 mu M) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 +/- 11 mu M) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 +/- 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max) = -6.7 +/- 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 +/- 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 +/- 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 +/- 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues.Conclusions: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.