The Intraocular Pressure Lowering Effect of a Dual Kinase Inhibitor (ITRI-E-(S)4046) in Ocular Hypertensive Animal Models
| Autor: | Chiu-Lien Hung, Ming-Chun Lin, Shuen-Hsiang Chou, Yu Chuan Huang, Chih-Peng Liu, Chih-Hung Chen, Chrong-Shiong Hwang, Yi-Hsun Chen, Chih-Wei Fu, Yen-Jen Wang, Da-Wen Lu, Meng-Ping She, Chia-Yi Yang, Felice Cheng, Wan-Ying Lin, Chia-Mu Tu, Wan Yu Ho, Hui-Ling Cheng |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Intraocular pressure Myosin light-chain kinase genetic structures Ocular hypertension Glaucoma Pharmacology Benzoates Tonometry Ocular In vivo Animals Humans Medicine ROCK1 Protein kinase A Myosin-Light-Chain Kinase Intraocular Pressure new glaucoma medications New Developments in Vision Research Sulfonamides rho-Associated Kinases business.industry Kinase trabecular meshwork Calcium-Binding Proteins dual kinase inhibitor Isoquinolines medicine.disease animal models eye diseases Disease Models Animal beta-Alanine Macaca Ocular Hypertension Rabbits sense organs business |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 |
| DOI: | 10.1167/iovs.62.13.12 |
| Popis: | Purpose The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP). Methods ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines. Results ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia. Conclusions ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma. |
| Databáze: | OpenAIRE |
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