Medicine for preventing or treating ophthalmic disease associated with enhanced intraocular neovascularization and/or intraocular vascular permeability

A technology of vascular permeability and angiogenesis, which can be applied to cardiovascular system diseases, sensory diseases, drug combinations, etc., and can solve problems such as ophthalmic diseases

Inactive Publication Date: 2020-09-18
KYOTO UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As its effect, it has been shown that S1P receptor agonists reduce the number of macrophages infiltrating into the wall of cerebral aneurysm by inhibiting the permeability of vascular endothelial cells, but there is no record of its application to ophthalmic diseases

Method used

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  • Medicine for preventing or treating ophthalmic disease associated with enhanced intraocular neovascularization and/or intraocular vascular permeability
  • Medicine for preventing or treating ophthalmic disease associated with enhanced intraocular neovascularization and/or intraocular vascular permeability
  • Medicine for preventing or treating ophthalmic disease associated with enhanced intraocular neovascularization and/or intraocular vascular permeability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] (Example 1) Effect on laser-induced choroidal neovascularization (choroidal neovascularization, CNV) model

[0155] (1) Evaluation of fundus fluorescein angiography (FA) grade

[0156] The right eye of an 8-week-old mouse (Nippon SLC, C56BL / 6J strain) was instilled with Mydrin P eye drops (Santen Pharmaceutical, Mydrin is a registered trademark) to dilate the pupil. The 7:1 mixed anesthetic solution of ketamine and xylazine was diluted 10 times with normal saline, and 10 mL / kg of the resulting solution was administered to the thigh muscle. Then, eye drops were instilled with Hyalein (registered trademark) eye drops 0.1% (Santen Pharmaceutical Co., Ltd.) so as not to dry the eyeballs.

[0157] Then, put the cover glass close to the right eye to observe the fundus, and use a laser photocoagulation device (MC500; NIDEKCO.LTD, Aichi, Japan) to irradiate 6 parts of the laser at equal intervals on the circumference of the optic nerve head (wavelength : 647nm, spot size: 50μ...

Embodiment 2

[0170] (Example 2) to the effect of retinal vein occlusion (RVO) model

[0171] Eight-week-old mice (Nippon SLC, ddy series) were anesthetized by intramuscularly administering 10 mL / kg of a mixed anesthetic solution diluted to ketamine (120 mg / kg) and xylazine (6 mg / kg). Then, 0.15 mL of rose bengal (20 mg / kg; WAKO) was administered into the tail vein, and the retinal vein was occluded by irradiating laser light to the vein three papillary from the optic nerve head in the right eye of the mouse. It should be noted that, when blocked, 10 to 15 laser irradiations are performed on one vein. For laser irradiation, an accessory (wavelength: 532 nm, spot size: 50 μm, irradiation time: 5000 ms, laser output power: 50 mW) of the fundus imaging device Micron4 (Phoenix Research Laboratories, Inc., Preston, CA, USA) was used. Three veins were occluded in each eye, and complete occlusion of the veins after laser irradiation was confirmed by fundus photographs.

[0172] Compound 1 was su...

reference example 1

[0175] (Reference Example 1) Correlation with Lymphopenia

[0176] For 7-week-old mice (Japan SLC Company, C57BL / 6J series), compound 1 suspended in a solvent (0.5% MC solution) was used at 0.003, 0.01, 0.03, 0.1, 0.3 or 1 mg / kg (free body conversion) The same dosage as in Example 1 was repeatedly administered orally once a day for 14 days. As a control, only solvent was administered (solvent group). Experiments were carried out using 5 cases respectively.

[0177] At 24 hours after the final administration, blood was collected from a large abdominal vein using a heparin-treated syringe under isoflurane anesthesia, and mixed with dipotassium ethylenediaminetetraacetic acid (EDTA·2K) (1 mg). The number of lymphocytes in the collected blood was measured using XT-2000iv (Sysmex). show the result in Figure 4 (a). Compound 1 significantly decreased lymphocytes in peripheral blood at 0.1 mg / kg or more, but no significant effect was confirmed at 0.03 mg / kg.

[0178] Next, for ...

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Abstract

Provided is a medicine for preventing or treating an ophthalmic disease associated with enhanced intraocular neovascularization and / or intraocular vascular permeability. The present inventors have made studies on medicines for preventing or treating ophthalmic diseases associated with enhanced intraocular neovascularization and / or intraocular vascular permeability. As a result, it is confirmed that a selective S1P receptor agonist having an agonistic activity on a S1P1 receptor has an activity to prevent intraocular neovascularization and an activity to prevent intraocular vascular permeability, and the present invention is accomplished. A compound according to the present invention, which is a selective S1P receptor agonist having an agonistic activity on a S1P1 receptor or a pharmaceutically acceptable salt thereof has an activity to prevent intraocular neovascularization and intraocular vascular permeability, and can be used as a prophylactic and / or therapeutic agent for exudative age-related macular degeneration, diabetic retinopathy, diabetic macular edema, myopic choroidal neovascularization, retinal artery occlusion, retinal vein occlusion, neovascular glaucoma or the like.

Description

technical field [0001] The present invention relates to a medicine for preventing or treating ophthalmic diseases accompanied with intraocular angiogenesis and / or hyperpermeability of intraocular blood vessels. [0002] This application claims priority based on Japanese Patent Application No. 2018-016911 incorporated herein by reference. Background technique [0003] Various ophthalmic diseases are known to be accompanied by intraocular angiogenesis or hyperpermeability of intraocular blood vessels. For example, age-related macular degeneration is a degenerative disease of the macula of the retina that accompanies aging, and is an intractable ophthalmic disease accompanied by severe vision loss. Age-related macular degeneration is classified into "exudative type" in which vision loss occurs rapidly with undesired choroidal neovascularization, and "atrophic type" in which vision loss occurs slowly due to atrophy of visual cells without choroidal neovascularization type". T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/135A61K31/397A61K31/403A61K31/4245A61K31/426A61K31/496A61P9/10A61P27/02
CPCA61K31/4245A61K31/426A61P9/10A61P27/02A61K31/397A61K31/496A61K31/137A61K31/41A61K9/0048A61K31/453A61K31/403A61K31/135A61K31/4184A61K31/54A61K45/06
Inventor 原英彰成宫周青木友浩荒森一朗山本梨绘
Owner KYOTO UNIV
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