[go: up one dir, main page]

WO2025232814A1 - Utilisation d'un antagoniste du récepteur a2a de l'adénosine pour le traitement et la prévention du glaucome - Google Patents

Utilisation d'un antagoniste du récepteur a2a de l'adénosine pour le traitement et la prévention du glaucome

Info

Publication number
WO2025232814A1
WO2025232814A1 PCT/CN2025/093324 CN2025093324W WO2025232814A1 WO 2025232814 A1 WO2025232814 A1 WO 2025232814A1 CN 2025093324 W CN2025093324 W CN 2025093324W WO 2025232814 A1 WO2025232814 A1 WO 2025232814A1
Authority
WO
WIPO (PCT)
Prior art keywords
glaucoma
adenosine
receptor antagonist
drug
intraocular pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/093324
Other languages
English (en)
Chinese (zh)
Inventor
陈江帆
张莉平
范宇晨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eye Hospital of Wenzhou Medical University
Original Assignee
Eye Hospital of Wenzhou Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eye Hospital of Wenzhou Medical University filed Critical Eye Hospital of Wenzhou Medical University
Publication of WO2025232814A1 publication Critical patent/WO2025232814A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • This disclosure belongs to the field of pharmaceutical technology, specifically relating to the field of ophthalmic drugs, and in particular to a novel use of adenosine A2A receptor antagonists in the treatment and prevention of glaucoma, which can reduce intraocular pressure in glaucoma patients and protect the optic nerve, thereby being applied to the treatment and prevention of the ophthalmic disease glaucoma.
  • POAG Primary open-angle glaucoma
  • TM trabecular meshwork
  • TGF- ⁇ 2 transforming growth factor- ⁇ 2
  • intraocular pressure-lowering drugs fall into two main categories: one category consists of drugs that inhibit aqueous humor production, such as beta-blockers (e.g., timolol, levobunolol hydrochloride) and carbonic anhydrase inhibitors (e.g., brinzolamide eye drops, acetazolamide tablets); the other category consists of drugs that promote aqueous humor outflow through the uvea and sclera, such as alpha-receptor agonists (including carteolol hydrochloride eye drops, betalol hydrochloride eye drops) and prostaglandin derivatives (e.g., latanoprost eye drops, travoprost eye drops).
  • beta-blockers e.g., timolol, levobunolol hydrochloride
  • carbonic anhydrase inhibitors e.g., brinzolamide eye drops, acetazolamide tablets
  • Glaucoma surgery lowers intraocular pressure by re-establishing pathways to guide aqueous humor outflow.
  • current treatments often offer only temporary relief. While they can temporarily lower intraocular pressure in glaucoma patients, they do not address the underlying issue of aqueous humor outflow obstruction from the trabecular meshwork. Therefore, they are essentially treating the symptoms, not the root cause. Due to these limitations, patients typically require lifelong medication. However, long-term use of these medications may worsen the obstruction of aqueous humor outflow, leading to drug resistance and ultimately requiring surgical intervention. After surgery, approximately 45% of patients experience poor outcomes due to scarring of the filtration tract.
  • Adenosine A2A receptor antagonists show potential in exploring new treatment strategies.
  • A2A receptor antagonists especially itratheline (KW6002)
  • KW6002 itratheline
  • A2A receptor antagonists such as KW6002
  • PD Parkinson's disease
  • Pinna et al. (2005) showed that A2A receptor antagonists, such as KW6002, can improve motor disorders without causing dyskinesia and can counteract the tremor of Parkinson's disease.
  • Adenosine A2A receptor antagonists were approved by the US FDA for the treatment of Parkinson's disease in August 2019. Beyond PD treatment, Ferré et al.
  • A2A receptor antagonists beyond pathological conditions such as drug addiction, sleep disorders, and pain management (Ferré, Diamond, Goldberg, Yao, Hourani, Huang, Urade, & Kitchen, 2007).
  • Merighi et al. (2021) published recent advances of A2A receptor antagonists in areas such as inflammation, asthma, chronic obstructive pulmonary disease (COPD), myocardial perfusion imaging, sepsis, rheumatoid arthritis, and wound healing.
  • COPD chronic obstructive pulmonary disease
  • This disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of medicaments for the treatment and/or prevention of ocular glaucoma diseases.
  • the medicaments of this disclosure demonstrate significant application potential in the field of anti-glaucoma treatment, particularly in the treatment and/or prevention of trabecular meshwork fibrosis and in reducing intraocular pressure caused by primary open-angle glaucoma (POAG).
  • POAG primary open-angle glaucoma
  • the ocular glaucoma diseases described in this disclosure include primary glaucoma, secondary glaucoma, mixed primary and secondary glaucoma, or normal-tension glaucoma.
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of a medicament for the treatment and/or prevention of ophthalmic glaucoma, wherein the adenosine A2A receptor antagonist includes itratheline KW6002.
  • this disclosure provides an adenosine A2A receptor antagonist for the treatment and/or prevention of ophthalmic glaucoma, wherein the adenosine A2A receptor antagonist comprises itratheline KW6002.
  • this disclosure provides a method for treating and/or preventing ophthalmic glaucoma, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of a drug that reduces intraocular pressure caused by disease.
  • this disclosure provides an adenosine A2A receptor antagonist for reducing abnormally high intraocular pressure caused by disease, wherein the adenosine A2A receptor antagonist includes itratheline KW6002.
  • this disclosure provides a method for reducing abnormally high intraocular pressure caused by a disease, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of an inhibitory drug for the treatment and/or prevention of trabecular meshwork fibrosis.
  • this disclosure provides an adenosine A2A receptor antagonist for the treatment and/or prevention of trabecular meshwork fibrosis, wherein the adenosine A2A receptor antagonist comprises itratheline KW6002.
  • this disclosure provides a method for treating and/or preventing trabecular meshwork fibrosis, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • this disclosure provides a pharmacological use of an adenosine A2A receptor antagonist, focusing on the treatment and/or prevention of ophthalmic glaucoma.
  • an adenosine A2A receptor antagonist By precisely targeting and modulating the activity of the adenosine A2A receptor, the drug of this disclosure demonstrates significant application potential in the field of anti-glaucoma treatment, particularly in the treatment and/or prevention of trabecular meshwork fibrosis and in reducing intraocular pressure and protecting the optic nerve in primary open-angle glaucoma (POAG).
  • POAG primary open-angle glaucoma
  • this disclosure provides the use of adenosine A2A receptor antagonists in the preparation of drugs for the treatment and prevention of trabecular meshwork fibrosis, their use in the preparation of drugs for reducing intraocular pressure in primary open-angle glaucoma (POAG), and their use in protecting optic nerve damage in glaucoma patients.
  • POAG primary open-angle glaucoma
  • Glaucoma particularly primary open-angle glaucoma (POAG) is a common eye disease characterized by persistently elevated intraocular pressure, which can lead to damage to retinal ganglion cells and vision loss.
  • POAG primary open-angle glaucoma
  • trabecular meshwork fibrosis is a key factor that obstructs aqueous humor outflow, thereby causing elevated intraocular pressure.
  • Trabecular meshwork fibrosis is a key factor in the pathological process of glaucoma, leading to obstructed aqueous humor outflow and increased intraocular pressure.
  • the medication disclosed herein by treating and/or preventing trabecular meshwork fibrosis, reduces the accumulation of extracellular matrix in the trabecular meshwork, promotes normal aqueous humor flow, thereby effectively lowering intraocular pressure and preventing or slowing the progression of glaucoma.
  • the drug described in this disclosure exhibits extremely high efficacy in lowering high intraocular pressure caused by ophthalmic diseases such as primary open-angle glaucoma (POAG), but is not limited to POAG; it can also be used for the treatment of glaucoma with normal intraocular pressure.
  • POAG primary open-angle glaucoma
  • blocking adenosine A2A receptors can also protect retinal ganglion cells and prevent vision loss.
  • This disclosure also relates to the use of drugs for treating and/or preventing trabecular meshwork fibrosis, which not only effectively lower intraocular pressure but also fundamentally improve the pathological conditions that lead to elevated intraocular pressure, providing patients with a safe and effective treatment option.
  • This disclosure also relates to the use of inhibiting aqueous humor production.
  • the disclosed drug can effectively lower intraocular pressure within half an hour, indicating that this effect is achieved by inhibiting aqueous humor production, providing patients with a safe, effective and rapid intraocular pressure-lowering treatment option.
  • This disclosure also relates to the use of drugs that directly protect retinal ganglion cells.
  • the disclosed drug can effectively protect retinal ganglion cells in glaucoma patients, providing a safe and effective treatment option for the recovery of patients' vision.
  • the drug described in this disclosure contains an effective amount of the active ingredient of an adenosine A2A receptor antagonist.
  • the adenosine A2A receptor antagonist includes itratheline KW6002.
  • Adenosine A2A receptor antagonists especially itratheline KW6002, effectively lower intraocular pressure by blocking A2A receptors, reducing the abnormal accumulation of extracellular matrix proteins in trabecular meshwork cells, inhibiting aqueous humor production, and promoting aqueous humor outflow.
  • this disclosure also relates to inhibitory drugs for the treatment and prevention of ocular fibrosis with abnormal accumulation of extracellular matrix proteins.
  • These drugs contain an effective amount of an active ingredient from an adenosine A2A receptor antagonist class of drugs and can be formulated in various forms such as tablets, capsules, pills, oral liquids, injections, eye drops, or ointments.
  • the aim is to effectively reduce intraocular pressure in glaucoma patients through multiple mechanisms and fundamentally improve the problem of extracellular matrix accumulation in the trabecular meshwork that leads to elevated intraocular pressure, thereby achieving a fundamental cure for glaucoma.
  • the adenosine A2A receptor antagonist drugs can lower intraocular pressure by transiently blocking A2A receptors.
  • This transient blockade can rapidly reduce aqueous humor production, making it an effective means of intraocular pressure control.
  • Itraphylline KW6002 as an example of this disclosure, demonstrates the potential to lower intraocular pressure in animal models by modulating A2A receptor activity.
  • the adenosine A2A receptor antagonist can block A2A receptors for a long period, reducing the accumulation of extracellular matrix in the trabecular meshwork, thereby increasing the looseness of the trabecular meshwork and lowering intraocular pressure. This long-term blockade helps achieve sustained intraocular pressure control and slow disease progression in glaucoma patients.
  • methods utilize the aforementioned adenosine A2A receptor antagonist drugs to directly protect retinal ganglion cells.
  • these drugs can directly protect retinal ganglion cells, slowing or preventing vision loss due to glaucoma.
  • Itratheline KW6002 has demonstrated potential neuroprotective effects in this regard.
  • this disclosure provides a formulation for treating and preventing ocular fibrosis caused by abnormal accumulation of extracellular matrix proteins, the formulation comprising an effective amount of an active ingredient of an adenosine A2A receptor antagonist.
  • Formulations include, but are not limited to, tablets, capsules, pills, oral solutions, injections, eye drops, or eye ointments.
  • the injection may be an intravenous injection, an intramuscular injection, a subcutaneous injection, a periorbital injection, a retrobulbar injection, a subconjunctival injection, a scleral injection, or an intraocular injection. This provides multiple routes of administration to meet the needs of different patients.
  • the drug further includes other active ingredients, including but not limited to:
  • Beta-blockers used to inhibit aqueous humor production
  • Carbonic anhydrase inhibitors used to reduce aqueous humor production
  • Alpha receptor agonists used to increase aqueous humor outflow
  • Prostaglandin derivatives used to promote the drainage of aqueous humor.
  • the other active ingredients are selected for combined use to provide a comprehensive treatment regimen for more comprehensive glaucoma treatment and/or prevention, particularly for patients with primary open-angle glaucoma (POAG).
  • POAG primary open-angle glaucoma
  • This combination therapy strategy aims to optimize treatment efficacy and reduce the development of drug tolerance by lowering intraocular pressure through multiple mechanisms, reducing trabecular meshwork fibrosis, and providing protection for retinal ganglion cells.
  • the formulation is an eye ointment, which is suitable for topical application and can act directly on the eye to provide a sustained drug release, thereby effectively reducing intraocular pressure and alleviating glaucoma symptoms. It is used once every night before bedtime to provide overnight efficacy. The long-lasting properties of the eye ointment make it an ideal choice for nighttime treatment, providing a sustained drug release during the patient's sleep and reducing the possibility of increased intraocular pressure upon waking in the morning.
  • excipients may be added to the ointment formulation, including but not limited to bases such as paraffin, lanolin, or white petrolatum, to provide long-lasting drug release and increase the duration of drug retention in the eye; the base not only provides the required viscosity and consistency but also reduces evaporation from the ocular surface, increasing patient comfort after use; in addition, the excipients may also include antioxidants such as vitamin E to protect the active ingredients from oxidative decomposition, thereby extending the shelf life of the formulation.
  • bases such as paraffin, lanolin, or white petrolatum
  • the formulation is an eye drop, which is convenient for patient self-management, can quickly penetrate into the eye tissue, and achieve an immediate effect of lowering intraocular pressure. It is administered 2 to 4 times a day to maintain intraocular pressure within the ideal range.
  • excipients may be added to the eye drop formulation, including but not limited to: thickeners such as sodium carboxymethyl cellulose to increase the retention time of the eye drops; lubricants and humectants such as glycerin or propylene glycol to improve patient comfort; preservatives such as benzalkonium bromide or chlorhexidine to ensure the microbiological stability of the formulation; and buffers such as phosphate buffer solutions to maintain the pH value of the eye drops close to that of human tears, thereby reducing irritation during administration.
  • thickeners such as sodium carboxymethyl cellulose to increase the retention time of the eye drops
  • lubricants and humectants such as glycerin or propylene glycol to improve patient comfort
  • preservatives such as benzalkonium bromide or chlorhexidine to ensure the microbiological stability of the formulation
  • buffers such as phosphate buffer solutions to maintain the pH value of the eye drops close to that of human tears, thereby reducing irritation during administration.
  • the formulation is an injection, including intravenous injections, intramuscular injections, subcutaneous injections, periocular injections, retroocular injections, subconjunctival injections, scleral injections, and intraocular injections.
  • injectable formulations are suitable for patients requiring more precise dosage control or those with more severe cases, providing multiple routes of administration to suit different patient needs and medical conditions.
  • concentration range of the injection injection-induced discomfort can be reduced, achieving effective therapeutic effects while minimizing potential eye irritation; this method of administration is suitable for patients requiring rapid reduction of intraocular pressure or those who do not respond well to eye drops.
  • excipients may be added to the injection, including but not limited to: solvents such as physiological saline or sterile water to ensure the physiological compatibility of the formulation and safety during injection; emulsifiers such as lecithin to prepare an emulsion to meet the needs of better bioavailability or specific administration sites; antioxidants such as sodium ascorbate or chelating agents such as EDTA to improve the stability of the formulation; and local anesthetics such as lidocaine to reduce injection pain.
  • solvents such as physiological saline or sterile water to ensure the physiological compatibility of the formulation and safety during injection
  • emulsifiers such as lecithin to prepare an emulsion to meet the needs of better bioavailability or specific administration sites
  • antioxidants such as sodium ascorbate or chelating agents such as EDTA to improve the stability of the formulation
  • local anesthetics such as lidocaine to reduce injection pain.
  • the composition or formulation is used to treat human or non-human mammals.
  • KW6002 By blocking A2A receptors, itratheline KW6002 rapidly inhibits aqueous humor production, thereby quickly lowering intraocular pressure.
  • KW6002 can significantly reduce intraocular pressure in a short period, with effects comparable to existing intraocular pressure-lowering drugs (such as latanoprost and timolol eye drops), and even exceeding existing treatments in some conditions. This rapid response is particularly important for acute hypertonic intraocular pressure events, effectively alleviating symptoms and preventing further visual impairment.
  • Blocking A2A receptors not only helps lower intraocular pressure but also directly protects retinal ganglion cells and preserves their projections to the lateral geniculate body and the superior colliculus of the brain. This direct neuroprotective effect is particularly important for the prevention and treatment of glaucoma-related neurodegeneration, helping to maintain vision and slow disease progression.
  • itratheline KW6002 as an adenosine A2A receptor antagonist, demonstrates significant advantages in glaucoma treatment. It not only rapidly lowers intraocular pressure but also fundamentally improves trabecular meshwork function and reduces fibrosis, thus achieving long-term intraocular pressure control. More importantly, it provides direct protection for retinal ganglion cells, a unique and significant advantage in traditional glaucoma treatment. Through studies in cell and animal models, itratheline KW6002 has demonstrated its multiple potentials in glaucoma treatment, providing a solid scientific foundation and new therapeutic directions for future clinical applications.
  • Figure 1 shows a comparison of cell morphology, displaying microscopic images of normal human trabecular meshwork cells at 0 hours, 24 hours, and 48 hours in different experimental groups.
  • Figure 2 shows a bar graph of matrix protein expression.
  • the expression levels of fibronectin (FN) and smooth muscle actin ( ⁇ -SMA) in each experimental group were detected by Western blotting.
  • Figure 3 shows immunofluorescence images of cellular protein expression, with fluorescence micrographs showing the fluorescent labeling of FN and ⁇ -SMA in different experimental groups.
  • Figure 4 shows the trend of intraocular pressure changes in mice in the KW6002 intervention group after immediate administration of KW6002 following modeling.
  • Figure 5 shows the trend of intraocular pressure changes in mice in the KW6002 treatment group after administration began on day 14 of modeling.
  • Figure 6 shows a morphological analysis of ocular tissue, illustrating the potential effects of KW6002 on ocular structures, including the cornea, trabecular meshwork (TM), and ciliary body (CB), through microscopic tissue section photographs.
  • Figure 7 shows the trend of intraocular pressure changes in different treatment groups (including treatment groups with different concentrations of KW6002 and the model group).
  • Figure 8 shows a statistical chart of treatment effects, demonstrating the comparison of intraocular pressure at a specific time point (half an hour after eye drops) in different treatment groups.
  • Figure 9 shows a comparison between KW6002 eye drops and existing drugs, comparing the differences between KW6002 eye drops and existing intraocular pressure-lowering drugs (latanoprost and timolol eye drops) in terms of intraocular pressure-lowering amplitude, onset time and duration.
  • Figure 10 shows the results of KW6002 eye drops in promoting aqueous humor outflow and a comparison with existing drugs.
  • Figure 11 shows the results of KW6002 eye drops in inhibiting aqueous humor production and a comparison with existing drugs.
  • Figures 12 and 13 show the experimental results of KW6002 on retinal ganglion cells after overactivation of n-methyl-d-aspartate (NMDA) receptors;
  • Figure 12 shows the staining patterns of surviving retinal ganglion cells (RGCs) in the central and peripheral regions of the retina, and
  • Figure 13 shows the comparison of the number of surviving RGCs through statistical analysis.
  • NMDA n-methyl-d-aspartate
  • Figures 14 and 15 show the experimental results of KW6002 on retinal structure after overactivation of NMDA receptors; Figure 14 shows the qualitative assessment of retinal structure, and Figure 15 shows the quantitative measurement results of ganglion cell complex (GCC) and retinal thickness in the central and peripheral regions of the retina.
  • GCC ganglion cell complex
  • Figure 16 shows the measurement results of CBT labeling intensity in retinal ganglion cells projecting from the retina to the lateral geniculate nucleus (LGN) and superior colliculus (SC).
  • LGN lateral geniculate nucleus
  • SC superior colliculus
  • adenosine A2A receptor antagonist refers to a class of compounds that competitively bind to the adenosine A2A receptor, thereby preventing adenosine from exerting its effects through the receptor. These compounds, by blocking the activation of the adenosine A2A receptor, can regulate a variety of physiological processes, including but not limited to inflammatory responses, neuroprotection, and the secretion of extracellular matrix proteins.
  • IOP intraocular pressure
  • Normal Trabecular Meshwork Cells refers to cells derived from the trabecular meshwork region of the human eye, which play a crucial role in maintaining intraocular pressure and aqueous humor flow.
  • NTM Normal Trabecular Meshwork Cells
  • dysfunction of trabecular meshwork cells can lead to impaired aqueous humor outflow, resulting in elevated intraocular pressure. Therefore, modulating the behavior and function of these cells could be a potential strategy for treating glaucoma.
  • trabecular meshwork fibrosis refers to the abnormal proliferation and hardening of fibrous tissue within the trabecular meshwork structure. This process leads to obstruction of the aqueous humor outflow channels, resulting in increased intraocular pressure. Trabecular meshwork fibrosis is one of the key pathological processes in glaucoma development.
  • POAG primary open-angle glaucoma
  • the term "itratheline KW6002" refers to a specific adenosine A2A receptor antagonist compound. It has shown potential therapeutic activity for a variety of diseases in multiple studies, including glaucoma treatment by regulating intraocular pressure.
  • TGF ⁇ 2 Transforming Growth Factor- ⁇ 2
  • TGF ⁇ 2 Transforming Growth Factor- ⁇ 2
  • extracellular matrix refers to the complex network structure outside cells, composed of various proteins and polysaccharides, which supports the structure of cells and tissues and participates in intercellular communication.
  • ECM extracellular matrix
  • trabecular meshwork cells the accumulation and abnormal changes of ECM can lead to trabecular meshwork fibrosis, affecting aqueous humor flow and being one of the important factors contributing to elevated intraocular pressure in glaucoma.
  • extracellular matrix (ECM) proteins specifically refers to the protein components that make up the extracellular matrix, such as fibronectin (FN) and ⁇ -smooth muscle actin ( ⁇ -SMA). These proteins play a crucial role in ECM accumulation and trabecular meshwork fibrosis. Therefore, regulating the expression and function of these ECM proteins can directly affect the structure and function of the trabecular meshwork, thereby having a positive effect on the treatment of glaucoma.
  • transient blockade refers to a drug's immediate (e.g., within 24 hours) and rapid action following intervention, temporarily blocking the activity of a specific receptor and thus rapidly affecting related physiological processes.
  • adenosine A2A receptor antagonists can bind to A2A receptors for a short period, resulting in transient blockade of their activity and achieving a significant reduction in intraocular pressure (IOP) within a short time (e.g., a reduction of more than 20% within one week).
  • IOP intraocular pressure
  • long-term blockade refers to a situation where a drug, after continuous administration (e.g., at least once daily), acts on a specific receptor for a prolonged period (e.g., weeks to months) to persistently inhibit its activity.
  • long-term blockade of A2A receptors can achieve long-term maintenance of reduced or hypotony (e.g., maintaining a reduction of more than 20% in IOP relative to pre-treatment levels) by continuously affecting the accumulation of extracellular matrix in trabecular meshwork through several weeks of drug treatment, and has the potential to provide long-term protection against retinal ganglion cells.
  • the term "effective dose” refers to a dosage of medicine sufficient to produce the desired therapeutic effect without causing unacceptable side effects.
  • the specific value of the effective dose may vary depending on the patient's individual circumstances (such as age, weight, disease severity, etc.).
  • the term "pharmaceutical formulation” refers to the physical form and formulation of a drug, including but not limited to tablets, capsules, pills, oral solutions, injections, eye drops, or eye ointments. Different formulations are suitable for different routes of administration and therapeutic goals.
  • formulation refers to a complete pharmaceutical preparation containing an active pharmaceutical ingredient, which can be solid, liquid, or semi-solid, and is designed for a specific application to treat, prevent, or diagnose a disease.
  • Formulations may include not only the active ingredient but also various inactive ingredients, i.e., excipients, to improve the stability, bioavailability, acceptability, and ease of administration of the drug.
  • the term "pharmaceuticalally acceptable excipient” refers to an inactive ingredient that is relatively harmless to humans and is used in the pharmaceutical industry to improve the physical, chemical properties, or efficacy of drug formulations.
  • excipients include, but are not limited to, fillers, stabilizers, solvents, lubricants, emulsifiers, colorants, fragrances, humectants, preservatives, and carriers. They are used in the manufacture of drug formulations, such as tablets, capsules, solutions, suspensions, and emulsions, to ensure the efficacy, safety, and patient acceptability of the drug.
  • oral liquid refers to any liquid formulation designed to provide a therapeutic effect through oral ingestion. These formulations may include solutions, suspensions, emulsions, or syrups, and are designed to improve oral bioavailability and patient compliance.
  • injection refers to a pharmaceutical preparation designed for administration via an injection route, such as intravenous, intramuscular, subcutaneous, or intraocular injection. Injections may be in the form of solutions, suspensions, or emulsions; they must be sterile and typically need to be contained in a sealed container suitable for single use, such as an ampoule or a pre-filled syringe.
  • eye drops refers to a liquid preparation specifically designed for application to the surface of the eye to treat or relieve eye diseases and symptoms. Eye drops provide a route for medication to act directly on the tissues of the eye and are used to treat glaucoma and other ophthalmic conditions.
  • eye ointment refers to a semi-solid formulation designed to be applied to the surface of the eye or eyelid to provide a sustained release of medication. Eye ointments are often used for nighttime treatment due to their longer stay in the eye, helping to improve symptoms and conditions of eye diseases.
  • RGCs spinal ganglion cells
  • Their axons form the optic nerve, responsible for transmitting visual information from the eye to the brain.
  • RGCs play a crucial role in light perception and the encoding and transmission of visual signals.
  • Their health is essential for maintaining visual function, while their damage or death is a marker of various vision-degenerative diseases, including glaucoma.
  • N-methyl-D-aspartic acid (NMDA) receptor refers to a type of glutamate receptor that exists in the central nervous system. When overactivated, it can lead to calcium overload and may cause cell damage or even cell death. This process is similar to the nerve damage mechanism in neurodegenerative diseases such as glaucoma.
  • central and peripheral retinal regions refer to different anatomical parts of the retina, where the central retinal region (Center) usually refers to the part around the macula and is responsible for central vision; the peripheral retinal region (Periphery) refers to the peripheral part of the retina and is associated with peripheral vision.
  • lateral geniculate nucleus refers to an important visual relay station in the brain, to which the axons of retinal ganglion cells project and transmit visual signals.
  • SC superiorior colliculus
  • CBT Chianged Block Tracking
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of a medicament for the treatment and/or prevention of ophthalmic glaucoma, wherein the adenosine A2A receptor antagonist includes itratheline KW6002.
  • this disclosure provides an adenosine A2A receptor antagonist for the treatment and/or prevention of ophthalmic glaucoma, wherein the adenosine A2A receptor antagonist comprises itratheline KW6002.
  • this disclosure provides a method for treating and/or preventing ophthalmic glaucoma, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of a drug to reduce intraocular pressure caused by disease, wherein the adenosine A2A receptor antagonist includes itratheline KW6002.
  • the disease is ophthalmic glaucoma or other eye diseases that require lowering intraocular pressure.
  • the disease is ophthalmic glaucoma.
  • this disclosure provides an adenosine A2A receptor antagonist for reducing abnormally high intraocular pressure caused by disease, wherein the adenosine A2A receptor antagonist includes itratheline KW6002.
  • the disease is ophthalmic glaucoma or other eye diseases that require lowering intraocular pressure.
  • the disease is ophthalmic glaucoma.
  • this disclosure provides a method for reducing abnormally high intraocular pressure caused by a disease, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • the disease is ophthalmic glaucoma or other eye diseases that require lowering intraocular pressure.
  • the disease is ophthalmic glaucoma.
  • the ophthalmic glaucoma disease is an ophthalmic disease that requires lowering intraocular pressure and/or optic nerve protection.
  • the ophthalmic glaucoma disease is primary glaucoma, secondary glaucoma, mixed primary and secondary glaucoma, or normal-tension glaucoma.
  • the primary glaucoma disease is primary open-angle glaucoma (POAG), angle-closure glaucoma, or a combination of open-angle and angle-closure glaucoma.
  • POAG primary open-angle glaucoma
  • angle-closure glaucoma or a combination of open-angle and angle-closure glaucoma.
  • the secondary glaucoma disease is inflammatory glaucoma, traumatic glaucoma, steroid glaucoma, cataract-associated glaucoma, or neovascular glaucoma.
  • the ophthalmic glaucoma disease is primary open-angle glaucoma (POAG), angle-closure glaucoma, and secondary glaucoma, etc.
  • POAG primary open-angle glaucoma
  • angle-closure glaucoma angle-closure glaucoma
  • secondary glaucoma etc.
  • the ophthalmic glaucoma disease is primary open-angle glaucoma (POAG).
  • POAG primary open-angle glaucoma
  • this disclosure provides the use of an adenosine A2A receptor antagonist in the preparation of an inhibitory drug for the treatment and/or prevention of trabecular meshwork fibrosis.
  • this disclosure provides an adenosine A2A receptor antagonist for the treatment and/or prevention of trabecular meshwork fibrosis, wherein the adenosine A2A receptor antagonist comprises itratheline KW6002.
  • this disclosure provides a method for treating and/or preventing trabecular meshwork fibrosis, the method comprising administering to a patient in need a therapeutically effective amount of an adenosine A2A receptor antagonist or a medicine containing an adenosine A2A receptor antagonist, said adenosine A2A receptor antagonist including itratheline KW6002.
  • the drug contains a therapeutically effective amount of an adenosine A2A receptor antagonist as an active ingredient.
  • the drug is capable of treating and/or preventing ophthalmic fibrosis with abnormal extracellular matrix proteins.
  • the drug is used to block A2A receptors, inhibit the expression of extracellular matrix proteins in trabecular meshwork cells, and reduce the abnormal accumulation of extracellular matrix in trabecular meshwork cells.
  • the drug is used to increase the looseness of the trabecular meshwork and reduce trabecular meshwork blockage.
  • the drug is used to inhibit aqueous humor production.
  • the drug is used to promote the drainage of aqueous humor.
  • the drug has a dual mechanism of action of promoting aqueous humor outflow and inhibiting aqueous humor production.
  • the drug can be used to provide protection for retinal cells.
  • the drug can be used to protect optic ganglion cells and prevent nerve damage caused by overactivation of NMDA receptors.
  • the mechanism of action of the adenosine A2A receptor antagonist itratheline KW6002 at the cellular level is investigated.
  • the regulatory effect of KW6002 on the expression of TGF ⁇ 2-induced extracellular matrix proteins in normal human trabecular meshwork (NTM) cells was explored.
  • itratheline KW6002 significantly inhibited TGF- ⁇ 2-induced morphological changes and migration-promoting effects in NTM cells. This indicates that KW6002 not only affects the expression of extracellular matrix proteins in trabecular meshwork cells but also regulates cell morphology and migration behavior, providing a potential new approach for the treatment of primary open-angle glaucoma.
  • KW6002 has been further confirmed, significantly reducing TGF ⁇ 2-induced FN and ⁇ -SMA expression and alleviating the accumulation of extracellular matrix proteins.
  • KW6002 is highlighted as an A2A receptor antagonist, inhibiting TGF ⁇ 2-activated signaling pathways by blocking A2A receptor activity, thereby slowing the fibrotic process of the trabecular meshwork extracellular matrix.
  • the drug is used to momentarily block and rapidly reduce intraocular pressure, or the drug is used to long-term block and reduce intraocular pressure over a prolonged period.
  • Some implementations focused on the effect of itratheline KW6002 on intraocular pressure (IOP) in POAG model mice and compared its efficacy with existing intraocular pressure-lowering drugs. Results showed that KW6002 eye drops significantly, rapidly, and persistently reduced IOP in model mice at various concentrations. Especially at high concentrations, the anti-intraocular pressure effect of KW6002 was comparable to that of mainstream latanoprost and timolol eye drops on the market, and even exhibited superior characteristics of rapid onset and long duration of action.
  • the dual mechanism of action of KW6002 has been fully demonstrated: promoting aqueous humor outflow and inhibiting aqueous humor production, providing a new perspective for the comprehensive treatment of glaucoma.
  • the drug further includes other active ingredients, including but not limited to: beta-blockers, carbonic anhydrase inhibitors, alpha-receptor agonists, and prostaglandin derivatives.
  • the ⁇ -receptor blocker is selected from one or more of timolol and levobunolol hydrochloride.
  • the carbonic anhydrase inhibitor is selected from one or more of brinzolamide and acetazolamide.
  • the ⁇ -receptor agonist is selected from one or more of carteolol hydrochloride and betaxolol hydrochloride.
  • the prostaglandin derivative is selected from one or more of latanoprost and travoprost.
  • the formulation of the drug is selected from tablets, capsules, pills, oral liquids, injections, eye drops, or eye ointments.
  • the formulation contains pharmaceutically acceptable excipients.
  • the formulation is an eye ointment, wherein the concentration of the adenosine A2A receptor antagonist itratheline KW6002 is 2-15 mM.
  • excipients may be added to the eye ointment, including one or more of antioxidants and a matrix.
  • the antioxidant is selected from one or more of paraffin wax, lanolin, and white petrolatum.
  • the antioxidant includes vitamin E.
  • excipients may be added to the eye drops, including one or more of thickeners, lubricants, humectants, preservatives, and buffers.
  • the thickener comprises sodium carboxymethyl cellulose.
  • the lubricant and/or wetting agent includes one or more of glycerin and propylene glycol.
  • the preservative includes one or more of benzalkonium bromide and chlorhexidine.
  • the buffer comprises a phosphate buffer solution.
  • the formulation is an injectable preparation, including intravenous injections, intramuscular injections, subcutaneous injections, periorbital injections, retroocular injections, subconjunctival injections, scleral injections, and intraocular injections.
  • excipients may be added to the injection, including one or more of solvents, emulsifiers, antioxidants, chelating agents, and local anesthetics.
  • the solvent includes one or more of physiological saline and sterile water.
  • the emulsifier includes lecithin.
  • the antioxidant includes sodium ascorbate.
  • the chelating agent includes EDTA.
  • the local anesthetic includes lidocaine.
  • the drug is a formulation in the form of tablets, capsules, pills, oral liquids, injections, eye drops, or eye ointments; further, the formulation contains pharmaceutically acceptable excipients.
  • excipients include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, and pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl
  • the drug is used to treat human or non-human mammals.
  • the drug is administered orally, parenterally (intravenously, intramuscularly), and topically, providing flexible treatment options to meet the needs of different patients.
  • the formulations disclosed herein can be capsules, tablets, pills, powders, and granules. These dosage forms can be optimized by adding various pharmaceutical additives such as fillers, binders, humectants, disintegrants, slowing agents, absorption accelerators, wetting agents, and adsorbents.
  • the pharmaceutical products of this disclosure can be prepared in physiologically acceptable sterile aqueous or anhydrous forms, dispersions, suspensions, or emulsions.
  • Suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyols, and suitable mixtures thereof.
  • Topical or drug-eluting dosage forms include ointments, powders, patches, sprays, and inhalers, suitable for direct treatment in specific situations. These dosage forms are formulated with consideration for the compatibility and stability of the active ingredient with physiologically acceptable carriers and, where necessary, other additives (such as preservatives and buffers).
  • this disclosure provides a comprehensive and effective drug treatment plan for the treatment of primary open-angle glaucoma, including a variety of choices in drug composition, dosage form and administration method to meet the treatment needs and preferences of different patients.
  • the drug disclosed herein through the design of multiple dosage forms and the combination of pharmaceutically acceptable excipients, provides a flexible and effective treatment option for primary open-angle glaucoma, aiming to optimize the patient's treatment experience while improving treatment outcomes.
  • the istradefylline KW6002 used in this embodiment has the structure shown in formula (I).
  • the drug is synthesized using vanillin as the starting material, first by methylation, Knoevenagel condensation, and chlorination under thionyl chloride to generate (E)-3,4-dimethoxycinnamoyl chloride.
  • This intermediate undergoes amidation with 1,3-diethyl-5,6-diaminouracil, followed by cyclization and methylation, ultimately synthesizing istradefylline (Reference: Duan Yumin, 2010).
  • Example 1 The regulatory mechanism of the adenosine A2A receptor antagonist itratheline KW6002 on the secretion of extracellular matrix proteins in normal human trabecular meshwork cells (NTM).
  • This experiment employed a cellular-level research approach, utilizing in vitro cell culture technology to investigate the effects of KW6002 on TGF ⁇ 2-induced expression of extracellular matrix proteins (such as fibronectin FN and smooth muscle actin ⁇ -SMA) in trabecular meshwork cells.
  • extracellular matrix proteins such as fibronectin FN and smooth muscle actin ⁇ -SMA
  • NTM Human normal trabecular meshwork cells
  • Blank control group trabecular meshwork cells cultured normally.
  • TGF ⁇ 2 (5ng/mL) was added to trabecular meshwork cells.
  • KW6002 control group 1 ⁇ M KW6002 was added to trabecular meshwork cells.
  • Trabecular meshwork cells were cultured for 48 hours, and the effect of itratheline KW6002 on TGF ⁇ 2-induced extracellular matrix protein secretion in trabecular meshwork cells was evaluated as follows:
  • This study aimed to evaluate the effects of itratheline KW6002 on the morphology of normal human trabecular meshwork (NTM) cells and its ability to block TGF- ⁇ 2-induced cell migration through cell morphology comparison images.
  • the experiment consisted of three groups: a blank control group, an experimental control group, and an experimental group. Cells in each group were observed and photographed under a microscope at 0, 24, and 48 hours after the start of the experiment. Microscopic images of cells from different experimental groups (blank control group, experimental control group, and experimental group) are provided to visually demonstrate the effect of KW6002 on cell morphology.
  • Figure 1 shows the morphological differences of cells in different experimental groups at 0, 24, and 48 hours.
  • the cells in the blank control group maintained stable morphology, exhibiting typical morphological characteristics of normal trabecular meshwork cells.
  • the experimental control group showed morphological changes upon TGF- ⁇ 2 stimulation, such as elongation of pseudopodia and expansion of the cell body, typical manifestations of enhanced cell migration.
  • cells supplemented with itratheline KW6002 showed a morphology closer to the blank control group than the control group, indicating that the addition of KW6002 can block TGF- ⁇ 2-induced morphological changes and migration-promoting behavior.
  • Cells in the KW6002 control group exhibited similar morphology and behavior to the blank control group, suggesting that KW6002 itself does not negatively affect the normal physiological state of trabecular meshwork cells.
  • extracellular matrix proteins in trabecular meshwork were detected using Western blotting with fibronectin antibody (Anti-FN) and smooth muscle actin antibody (Anti- ⁇ -SMA) to quantify the regulatory effect of itratheline KW6002 and further explore its potential in inhibiting extracellular matrix (ECM) protein accumulation.
  • Anti-FN fibronectin antibody
  • Anti- ⁇ -SMA smooth muscle actin antibody
  • Whole-cell proteins were extracted from trabecular meshwork cells in each experimental group. The extracted proteins were separated using SDS-PAGE, and the separated proteins were transferred onto PVDF membranes. Target proteins were detected by Western blotting using specific antibodies (Anti-FN and Anti- ⁇ -SMA). Image analysis software was used to quantify the expression levels of FN and ⁇ -SMA proteins in the experimental groups based on the intensity of the obtained immunoblot bands, thus quantifying the regulatory effect of KW6002.
  • Figure 3 shows fluorescence micrographs of different experimental groups, visually demonstrating the effect of KW6002 on the expression of specific proteins (FN and ⁇ -SMA).
  • the blank control group shows the baseline expression levels of FN and ⁇ -SMA, while the experimental control group showed significantly enhanced fluorescence signals of FN and ⁇ -SMA after the addition of TGF ⁇ 2, indicating that TGF ⁇ 2 stimulated the expression of ECM proteins.
  • Cells in the experimental groups treated with KW6002 showed weakened fluorescence signals compared to the experimental control group, indicating that KW6002 can alleviate the TGF ⁇ 2-induced increase in ECM protein expression.
  • Example 2 Effects of the adenosine A2A receptor antagonist itratheline KW6002 on intraocular pressure in a mouse model of primary open-angle glaucoma (POAG) and its potential alterations to ocular structure.
  • POAG primary open-angle glaucoma
  • KW6002 powder was dissolved in 10% DMSO and 90% Corn Oil to prepare a 5 mg/kg KW6002 solution.
  • Inclusion criteria 1 No eye disease. 2 Normal direct and indirect pupillary light reflexes in both eyes. Intraocular pressure (IOP) was measured and recorded regularly in both eyes while the mice were awake to ensure accurate IOP data before and after administration.
  • IOP Intraocular pressure
  • mice were anesthetized with isoflurane gas, and the weight of each mouse was measured.
  • High IOP was induced in the mouse model by TGF ⁇ 2 overexpression to simulate the pathological state of glaucoma.
  • the method involved injecting TGF ⁇ 2-overexpressing adenovirus into the vitreous cavity of model mice at a dose of 3 ⁇ l and a concentration of 3 ⁇ 108 pfu/ ⁇ l.
  • the same dose and concentration of empty adenovirus were injected into the vitreous cavity of the contralateral eye to establish a high intraocular pressure model.
  • Model group Mice received TGF ⁇ 2-overexpressing adenovirus injection to establish a high intraocular pressure model, but did not receive KW6002 treatment.
  • Low-dose KW6002 intervention group Mice were given an intraperitoneal injection of 1 mg/kg KW6002 immediately after the establishment of a high intraocular pressure model by injection of TGF ⁇ 2 overexpressing adenovirus (day 0). The drug was administered once daily.
  • High-dose KW6002 intervention group Mice were given an intraperitoneal injection of 5 mg/kg KW6002 immediately after the establishment of a high intraocular pressure model by injection of TGF ⁇ 2 overexpressing adenovirus (day 0). The administration was started immediately on day 0 after modeling and was once daily.
  • Low-dose KW6002 treatment group Mice were given an intraperitoneal injection of 1 mg/kg KW6002 after a TGF ⁇ 2-overexpressing adenovirus injection to establish an intraocular pressure model. The administration was started once daily after the intraocular pressure increased and stabilized (day 14 after modeling).
  • mice were injected with TGF ⁇ 2-overexpressing adenovirus to establish a hypertensive model, they were given an intraperitoneal injection of 5 mg/kg KW6002. Once the intraocular pressure increased and stabilized (day 14 after modeling), the drug was administered once daily.
  • Normal control group did not receive TGF ⁇ 2 overexpressing adenovirus injection, nor KW6002 treatment.
  • Figure 4 shows the trend of intraocular pressure (IOP) changes in mice after immediate administration of KW6002 in the intervention group.
  • IOP intraocular pressure
  • Figure 5 shows the trend of intraocular pressure (IOP) changes in mice in the treatment group after administration began on day 14 post-modeling.
  • IOP intraocular pressure
  • This experiment aimed to gain a deeper understanding of the effects of the adenosine A2A receptor antagonist itratheline KW6002 on ocular structures, particularly the trabecular meshwork, in a mouse model of primary open-angle glaucoma (POAG).
  • POAG primary open-angle glaucoma
  • mice in the normal control group, model group, high-dose KW6002 intervention group (5 mg/kg KW6002), and mice that did not establish a high intraocular pressure model but were injected with only 5 mg/kg KW6002 were fixed, dehydrated, cleared, embedded in paraffin, sectioned, and stained.
  • the ocular structures of each group were observed and photographed using an optical microscope, with particular attention paid to morphological changes in the trabecular meshwork region. The openness of the trabecular meshwork, the accumulation of extracellular matrix proteins, and cell arrangement were assessed and compared.
  • Figure 6 shows photographs of mouse ocular tissue sections.
  • the trabecular meshwork structure remained normal, with no obvious extracellular matrix accumulation or cell arrangement disorder, and the trabecular meshwork opening was high, indicating the normal structure and function of the trabecular meshwork in a healthy state.
  • the trabecular meshwork region showed obvious extracellular matrix protein accumulation and cell arrangement disorder, and the trabecular meshwork opening was reduced, indicating severe trabecular meshwork blockage. This is consistent with high intraocular pressure and is a key factor in the progression of POAG.
  • the mice in the KW6002 intervention group showed significantly reduced extracellular matrix accumulation in the trabecular meshwork region and significantly increased trabecular meshwork opening. This indicates that the application of KW6002 alleviated the blockage of the trabecular meshwork, facilitated the normal outflow of aqueous humor, and thus reduced intraocular pressure.
  • Example 3 Effects of adenosine A2A receptor antagonist itratheline KW6002 eye drops at different concentrations on intraocular pressure (IOP) in mice with primary open-angle glaucoma (POAG).
  • IOP intraocular pressure
  • POAG primary open-angle glaucoma
  • This embodiment aims to evaluate the effect of adenosine A2A receptor antagonist itratheline KW6002 eye drops at different concentrations on intraocular pressure (IOP) in mice with primary open-angle glaucoma (POAG) and to compare its efficacy with existing intraocular pressure-lowering drugs.
  • IOP intraocular pressure
  • POAG primary open-angle glaucoma
  • KW6002 powder was dissolved in 2% DMSO and 98% methylcellulose to prepare 2.6mM, 7.8mM, and 13mM KW6002 eye drops.
  • the KW6002 treatment group was given the drug immediately after the intraocular pressure of the model group increased and stabilized, once a day, 5uL per eye drop.
  • Model group Mice were injected with TGF ⁇ 2-overexpressing adenovirus to establish a high intraocular pressure model, but did not receive KW6002 eye drops treatment.
  • KW6002 treatment groups at different concentrations (2.6mM, 7.8mM, 13mM): After the high intraocular pressure model of mice stabilized, they began to receive KW6002 eye drops of the corresponding concentrations once a day.
  • mice did not receive injection of TGF ⁇ 2 overexpressing adenovirus, nor were they treated with KW6002 eye drops.
  • mice After the high intraocular pressure model was stabilized, mice began to receive existing intraocular pressure-lowering drugs, latanoprost and timolol eye drops (5 ⁇ L once daily).
  • IOP intraocular pressure
  • KW6002 eye drops were administered after daily IOP measurements to avoid any influence from medication. Additionally, all IOP measurements were performed at the same time to avoid the impact of diurnal variations on IOP.
  • the efficacy of KW6002 eye drops was compared with existing IOP-lowering drugs (latanoprost and timolol eye drops). The degree of IOP reduction, onset time, and duration of action were compared among the different drugs.
  • This experiment compares the intraocular pressure-lowering effects of KW6002 eye drops at different concentrations on mice with primary open-angle glaucoma (POAG), and compares its effects with those of current mainstream intraocular pressure-lowering drugs, aiming to evaluate the efficacy and potential clinical application value of KW6002.
  • POAG primary open-angle glaucoma
  • Figure 7 shows the changes in intraocular pressure (IOP) of mice at different time points before and after treatment in the 0.1%, 0.3%, and 0.5% (mass percentage) concentration groups of KW6002 eye drops, as well as in the model group.
  • IOP intraocular pressure
  • Figure 8 shows the comparison of intraocular pressure reduction in mice in the KW6002 treatment group (13 mM) and the positive control group half an hour after eye drops. The results indicate that the reduction in intraocular pressure by KW6002 eye drops at a concentration of 13 mM is comparable to that of the positive control drugs (latanoprost and timolol eye drops), demonstrating its rapid and effective intraocular pressure-lowering performance.
  • Figure 9 shows the intraocular pressure reduction magnitude, onset time, and duration of action of KW6002 eye drops compared to the positive control drug.
  • KW6002 eye drops exhibited a faster onset time and a longer duration of action, especially the 13mM concentration group, which showed significantly better sustained effect over 24 hours than the positive control drug, demonstrating its superior and long-lasting intraocular pressure-lowering effect.
  • This experiment aimed to analyze the effects of KW6002 eye drops on promoting aqueous humor outflow and inhibiting aqueous humor production, comparing it with existing drugs (latanoprost and timolol eye drops).
  • Fluorescence intensity is a key parameter used to quantify aqueous humor outflow and production.
  • the outflow rate of the fluorescently labeled substance after drug treatment was observed.
  • the inhibition of aqueous humor production the accumulation of the fluorescently labeled substance in the eye after drug treatment was observed.
  • Figure 10 shows the results of KW6002 eye drops in promoting aqueous humor outflow.
  • the relative fluorescence intensity of intraocular markers in the KW6002 treatment group was significantly lower than that in the model group, indicating that KW6002 effectively promoted aqueous humor outflow.
  • the decrease in fluorescence intensity in the KW6002 treatment group was comparable to that of the positive control drug latanoprost, suggesting that the effect of KW6002 in promoting aqueous humor outflow is no less than that of the known aqueous humor outflow promoter latanoprost.
  • Figure 11 shows the results of KW6002 eye drops in inhibiting aqueous humor production.
  • Mice in the KW6002 treatment group showed a significant decrease in fluorescence intensity compared to the model group, indicating that KW6002 helps inhibit aqueous humor production.
  • the fluorescence intensity in the KW6002 treatment group was not significantly different from that of the positive control drug timolol, suggesting that KW6002 is comparable to the known aqueous humor production inhibitor timolol in inhibiting aqueous humor production.
  • Example 4 Protection of retinal ganglion cells and their projections to the brain by the adenosine A2A receptor antagonist itratheline KW6002 in POAG model mice
  • This embodiment aims to verify the protective effect of the adenosine A2A receptor antagonist itratheline KW6002 on retinal ganglion cells (RGCs) and their projection pathway to the brain. It investigates whether KW6002 can protect retinal ganglion cells from damage caused by excessive activation of N-methyl-d-aspartate (NMDA) receptors.
  • NMDA N-methyl-d-aspartate
  • Example 2 mouse eyeball samples from the normal control group, model group, and high-dose KW6002 intervention group (5 mg/kg KW6002) were sectioned, stained, and labeled with retinoid cells (RGCs) for microscopic observation and analysis. Cell viability in different treatment groups was assessed by counting surviving RGCs in the stained retinal sections. Cell arrangement and hierarchical structure of retinal sections from different groups were observed and recorded, and image processing software was used to analyze retinal integrity and damage levels. Differences between the experimental and control groups were compared to determine the significant protective effect of KW6002.
  • RGCs retinoid cells
  • Figures 12 and 13 illustrate the protective effect of KW6002 on retinal ganglion cells after NMDA receptor overactivation.
  • Figure 12 shows microscopic images of dye-labeled RGCs, counting the number of surviving RGCs in the central and peripheral regions.
  • Figure 13 shows the statistically significant differences in the number of surviving RGCs between groups using ANOVA.
  • the normal control group shows the normal survival status of untreated RGCs, with fluorescence intensity representing the baseline of normal survival.
  • the survival rate of RGCs was significantly decreased compared to the normal control group, indicating that NMDA receptor overactivation led to a large number of retinal ganglion cell deaths.
  • the treatment group injected with KW6002 showed a significantly increased survival rate of RGCs in both the central and peripheral regions of the retina, especially in the central region, showing a highly significant increase compared to the model group (****, p ⁇ 0.0001).
  • KW6002 has a significant effect on protecting retinal ganglion cells, particularly against cell death induced by NMDA receptor overactivation.
  • These findings provide experimental evidence for KW6002 as a potential neuroprotective agent, especially in the treatment and prevention of neurodegenerative eye diseases such as glaucoma, where it has important clinical significance for protecting retinal ganglion cells.
  • Figures 14 and 15 illustrate the protective effect of KW6002 on retinal structure after overactivation of NMDA receptors.
  • Figure 14 shows in vivo retinal imaging obtained by optical coherence tomography (OCT) to assess retinal structure, qualitatively evaluating the integrity and arrangement of cell layers;
  • Figure 15 shows the statistical analysis results of quantitative measurements of the central and peripheral regions of the retina.
  • the normal control group shows the normal retinal structure without any treatment.
  • Ganglion cell complex (GCC) and retinal thickness remained within the normal range, reflecting the healthy state of the undamaged retina.
  • the model group showed damaged retinal structure, loose cell layer arrangement, reduced cell density, and significantly reduced mean thickness of ganglion cell complex (GCC) and retina, reflecting a common phenomenon in glaucoma.
  • GCC ganglion cell complex
  • the retinal structure after KW6002 treatment was closer to that of the normal control group, especially in terms of the integrity and arrangement of nerve cell layers, and the mean thickness of GCC and retina was also significantly increased compared with the model group.
  • KW6002 demonstrated a positive effect in preventing retinal cell damage and death, as well as a potential protective effect against retinal structural damage.
  • Statistical analysis showed that KW6002 significantly reduced retinal damage caused by NMDA receptor overactivation, providing an experimental basis for its potential role as a drug against neurodegenerative diseases.
  • KW6002 showed good efficacy in protecting the retinal ganglion cell layer and overall retinal thickness, which is of significant value for the treatment of retinal nerve damage diseases such as glaucoma.
  • Figure 16 illustrates the protective effect of KW6002 on retinal ganglion cell projection from the retina to the lateral geniculate nucleus (LGN) and superior colliculus (SC) after overactivation of NMDA receptors.
  • Figure 16 shows the tracking of cholera toxin B subunit (CTB) in the central and peripheral retinal regions. Slices of the LGN and SC from each experimental group were taken, and the CBT labeling intensity was measured as an indicator of the integrity and function of ganglion cell axonal projection.
  • the normal control group shows the CBT fluorescence intensity and distribution of the LGN and SC in the brain opposite the operated eye under normal conditions, serving as a reference for normal axonal projection.
  • the LGN and SC slices in the model group showed reduced CBT distribution density and decreased fluorescence intensity, indicating impaired axonal projection, consistent with optic nerve damage in diseases such as glaucoma. Furthermore, this trend was statistically significant in quantitative detection, indicating a significant deterioration in the survival and functional status of RGC axons in the model group.
  • the CBT labeling intensity of LGN and SC was similar to that of the normal control group, but significantly higher than that of the NMDA model group, especially in LGN, where the CBT labeling intensity was almost at the same level as that of the normal control group.
  • KW6002 helps protect the axons of retinal ganglion cells and prevents nerve damage caused by NMDA receptor overactivation.
  • the CBT labeling intensity data of LGN and SC demonstrate the potential of KW6002 in protecting key structures of the visual pathway.
  • KW6002 alleviates axonal damage to retinal ganglion cells caused by NMDA receptor overactivation and maintains the integrity of the visual transmission system.
  • These findings support the potential application of KW6002 in the treatment of glaucoma and other neurodegenerative diseases, particularly its effect on protecting the axons and function of retinal ganglion cells.
  • These results provide direct evidence of KW6002's protective effect on the optic nerve and visual transmission pathway, and provide a scientific basis for further exploring its potential application in the treatment of neurodegenerative diseases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente divulgation concerne un médicament pour la prévention et/ou le traitement du glaucome. Plus précisément, la présente invention concerne l'utilisation d'un antagoniste du récepteur A2A de l'adénosine pour le traitement et la prévention du glaucome. Le traitement et la prévention consistent à, sans s'y limiter, inhiber la production d'humeur aqueuse dans des cellules épithéliales non pigmentées du corps ciliaire, à réduire la pression intraoculaire élevée due à l'obstruction de l'écoulement d'humeur aqueuse en raison de la fibrose et de l'épaississement du réseau trabéculaire, à améliorer la fluidité de l'humeur aqueuse dans l'œil, à inhiber les changements pathologiques dans le réseau trabéculaire et à obtenir un effet protecteur sur les cellules rétiniennes. De plus, le médicament de la présente invention peut également contribuer à remédier au problème de tolérance aux médicament destinés au traitement du glaucome, permet d'abaisser la pression intraoculaire chez des patients atteints de glaucome et de fournir un effet protecteur sur les nerfs optiques, et fournit une stratégie plus efficace pour un traitement à long terme.
PCT/CN2025/093324 2024-05-08 2025-05-08 Utilisation d'un antagoniste du récepteur a2a de l'adénosine pour le traitement et la prévention du glaucome Pending WO2025232814A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410559987.4 2024-05-08
CN202410559987.4A CN118490691A (zh) 2024-05-08 2024-05-08 腺苷a2a受体拮抗剂在青光眼治疗及预防中的应用

Publications (1)

Publication Number Publication Date
WO2025232814A1 true WO2025232814A1 (fr) 2025-11-13

Family

ID=92247749

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/093324 Pending WO2025232814A1 (fr) 2024-05-08 2025-05-08 Utilisation d'un antagoniste du récepteur a2a de l'adénosine pour le traitement et la prévention du glaucome

Country Status (2)

Country Link
CN (1) CN118490691A (fr)
WO (1) WO2025232814A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120204234B (zh) * 2025-05-28 2025-08-19 温州医科大学附属眼视光医院 11β-HSD1通路活性抑制剂在制备治疗青光眼睫状体炎综合征药物上的应用

Also Published As

Publication number Publication date
CN118490691A (zh) 2024-08-16

Similar Documents

Publication Publication Date Title
US20070265247A1 (en) Method of reducing contact lens intolerance with non-drying antihistamines
RU2324483C2 (ru) Ингибиторы гистондеацетилазы для лечения дегенеративных заболеваний глаз
EP3886858B1 (fr) Composés pour le traitement de maladies des yeux associées à une vascularisation excessive
EP3808352A1 (fr) Utilisation d'un salidroside et d'un dérivé de celui-ci dans la préparation d'un médicament inhibiteur pour des maladies de fibrose ophtalmique provoquées par des anomalies de protéines matricielles extracellulaires
JP2025004186A (ja) 眼表面疼痛を治療する方法
WO2025232814A1 (fr) Utilisation d'un antagoniste du récepteur a2a de l'adénosine pour le traitement et la prévention du glaucome
RU2672057C2 (ru) Ингибитор хориоретинальных нарушений
WO2019024433A1 (fr) Composition ophtalmique à base d'un composé de mononitrate d'aminoamantadine, sa préparation et son application
CN115518036B (zh) 一种包含左旋咪唑的眼用药物组合物及其制备方法和应用
JP7002756B2 (ja) 局所と局部の麻酔と鎮痛
JP2020514347A (ja) チオトロピウムを有効成分として含有する近視予防、近視治療および／または近視進行抑制剤
KR20230098630A (ko) 노안의 예방, 제어 및 근절에 효과적인 저농도 투여량의 상승적 안과 조성물
JPWO2004004738A1 (ja) 角結膜上皮細胞障害治療薬又は予防薬
JPH11279062A (ja) 眼科用剤
JP2012250947A (ja) アデノシン誘導体とβ受容体遮断薬の組合せ剤
US20110245190A1 (en) Method for improving post surgery visual acuity outcome with azithromycin
Merli et al. Treatment: An Up to Date
HK40061312A (en) Compounds for treatment of eye diseases associated with excessive vascularisation
HK40061312B (en) Compounds for treatment of eye diseases associated with excessive vascularisation
WO2025140240A1 (fr) Composition pharmaceutique et méthode de traitement et/ou de prévention d'une lésion cornéenne
Lee et al. Medical therapy for glaucoma
WO2020166679A1 (fr) Composition pharmaceutique pour abaisser la pression intraoculaire
CN118056566A (zh) 一种调节神经病变的方法和药物组合物
Williamson et al. 14 Medical Therapy for Glaucoma
Mandić et al. Current management of open angle glaucoma