Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China.
Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Republic of China.
Invest Ophthalmol Vis Sci. 2019 Feb 1;60(2):624-633. doi: 10.1167/iovs.18-25252.
The purpose of this study was to investigate the IOP-lowering effects of the ITRI-E-212, a new Rho-associated protein kinase (ROCK) inhibitor. ITRI-E-212 improved fluid outflow through the trabecular meshwork and reduced IOP with transient and mild conjunctival hyperemia. ITRI-E-212 can potentially be developed into new antiglaucoma agents.
ITRI-E-212 was selected from more than 200 amino-isoquinoline structures because of its adequate solubility and drug-loading percentage in eye drops. ITRI-E-212 has less than 50% inhibitory concentration (IC50) against ROCK2. The in vitro kinase inhibition was evaluated using the ADP-Glo kinase assay. A comprehensive analysis of the kinase inhibitor selectivity of ITRI-E-212 was performed using the KINOMEscan methodology. The IOP-lowering effect and tolerability of ITRI-E-212 were investigated in normotensive and ocular hypertensive rabbits. The pharmacokinetics study was performed in vivo in the aqueous humor (AH), and hyperemia was assessed.
ITRI-E-212 showed high in vitro inhibitory activity against ROCK2 and high specificity against AGC kinases. The mean IOP-lowering effect of ITRI-E-212 in normotensive and ocular hypertensive models was 24.9% and 28.6%, respectively; 1% ITRI-E-212 produced notable reductions in IOP that were sustained for at least 6 hours after each dose once per day. Only transient, mild hyperemia was observed. The compound extracted from the AH reached 78.4% ROCK2 kinase inhibition at 1 hour after dose administration and was sustained for 4 hours.
ITRI-E-212 is a novel and highly specific ROCK2 inhibitor with the ability to lower IOP in animal models. It has favorable pharmacokinetic and ocular tolerability profiles with only minimal conjunctival hyperemia.
本研究旨在探讨新型 Rho 相关蛋白激酶（ROCK）抑制剂 ITRI-E-212 的降眼压作用。ITRI-E-212 通过增加房水流出小梁网来降低眼压，并伴有短暂、轻度的结膜充血。ITRI-E-212 可能成为新的抗青光眼药物。
从 200 多种氨基异喹啉结构中选择 ITRI-E-212，因其在滴眼剂中有足够的溶解度和载药量。ITRI-E-212 对 ROCK2 的半数抑制浓度（IC50）小于 50%。采用 ADP-Glo 激酶测定法评价其体外激酶抑制作用。采用 KINOMEscan 方法对 ITRI-E-212 的激酶抑制剂选择性进行全面分析。在正常眼压和高眼压兔中研究 ITRI-E-212 的降眼压作用和耐受性。在体内通过房水（AH）进行药代动力学研究，并评估充血情况。
ITRI-E-212 对 ROCK2 具有高体外抑制活性，对 AGC 激酶具有高特异性。在正常眼压和高眼压模型中，ITRI-E-212 的平均眼压降低作用分别为 24.9%和 28.6%；1%的 ITRI-E-212 可显著降低眼压，每天一次，每次给药后至少 6 小时眼压持续下降。仅观察到短暂、轻度的充血。在给药后 1 小时，从 AH 中提取的化合物达到 78.4%的 ROCK2 激酶抑制作用，并持续 4 小时。
ITRI-E-212 是一种新型的、高度特异的 ROCK2 抑制剂，能够降低动物模型的眼压。其具有良好的药代动力学和眼部耐受性，仅有轻微的结膜充血。
