A Highly Selective Rho-Kinase Inhibitor (ITRI-E-212) Potentially Treats Glaucoma Upon Topical Administration With Low Incidence of Ocular Hyperemia
| Autor: | Wan-Ru Chen, Lee Tze-Chung, Chia-Mu Tu, Yu Chuan Huang, Yi-Ling Hsu, Chrong-Shiong Hwang, Yi-Hsun Chen, Da-Wen Lu, Lin Chih-Lung, Cherng-Ru Hsu, Huang Kuo-Kuei, Chih-Hung Chen, Huang Jui-Wen, Meng-Nan Lin, Chih-Peng Liu, Shuen-Hsiang Chou |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Intraocular pressure Myosin Light Chains genetic structures Erythema Glaucoma Administration Ophthalmic Hyperemia Pharmacology Aqueous Humor 03 medical and health sciences 0302 clinical medicine Pharmacokinetics In vivo medicine Animals Phosphorylation Protein Kinase Inhibitors Antihypertensive Agents Intraocular Pressure 030304 developmental biology 0303 health sciences rho-Associated Kinases business.industry Incidence Eyelids medicine.disease Isoquinolines eye diseases Disease Models Animal medicine.anatomical_structure Tolerability Rho kinase inhibitor 030221 ophthalmology & optometry sense organs Trabecular meshwork Rabbits medicine.symptom Ophthalmic Solutions business Conjunctiva |
| Zdroj: | Investigative ophthalmologyvisual science. 60(2) |
| ISSN: | 1552-5783 |
| Popis: | Purpose 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. Methods 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. Results 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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