Methods for treatment of diabetic retinopathy and other ophthalmic diseases

Abstract

To provide: methods for treatment of ophthalmic diseases or disorders such as an ophthalmic disease or disorder associated with diabetes in a patient; methods of treating retinopathy of prematurity in a patient; and methods for treating wet age-related macular degeneration in a patient.SOLUTION: Methods comprise administration of compounds disclosed herein to a patient in need thereof that inhibit or slow one or more signs or symptoms of such conditions.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 61 / 781,907, filed March 14, 2013, U.S. Provisional Application No. 61 / 643,178, filed May 4, 2012, U.S. Provisional Application No. 61 / 643,051, filed May 4, 2012, and U.S. Provisional Application No. 61 / 643,058, filed May 4, 2012, which are incorporated by reference in their entireties. [Background technology]

[0002] Diabetic retinopathy is a common and specific microvascular complication of diabetes and the leading cause of preventable vision loss in working-age people. It is identified in one-third of diabetic patients and is associated with an increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease and heart failure. Optimal control of blood glucose, blood pressure and possibly blood lipids remains fundamental to reduce the risk of development and progression of retinopathy.

[0003] Retinopathy of prematurity (ROP) causes blindness in approximately 400-800 infants in the United States each year and reduces the vision of thousands more worldwide. It is an increasingly serious problem in developing countries because extremely low birth weight infants are at very high risk for ROP, even though steady improvements in neonatal intensive care units have increased survival rates for these infants.

[0004] The retina contains the photoreceptors that transmit light into nerve signals and also has an extensive vascular supply. The clinical hallmark of ROP is abnormalities in the retinal vasculature that appear at premature age. This abnormal vasculature provides an inadequate supply of oxygen during the maturation of rod photoreceptors (the most oxygen-demanding of any cell in the body). In the most severe cases of ROP, the primary cause of vision loss is retinal detachment due to leaching of retinal blood vessels. However, in milder cases of ROP, retinal vascular abnormalities usually resolve without treatment, but patients suffer from lifelong visual impairment even with optimal visual correction.

[0005] Age-related macular degeneration (AMD) is the leading cause of serious vision loss in people over the age of 55 in the United States. AMD occurs in either dry or (less commonly) wet forms. In wet AMD, blood vessels grow from the choriocapillaris (choroidal neovascularization or angiogenesis) through defects in Bruch's membrane and, in some cases, the basal retinal pigment epithelium. These blood vessels leak serous or hemorrhagic exudation mechanisms leading to the formation of fibrovascular scars in the macula accompanied by neuroretinal degeneration, detachment and tearing of the retinal pigment epithelium, vitreous hemorrhage, and permanent loss of central vision. This process is responsible for over 80% of cases of significant vision loss in AMD patients.

[0006] Choroidal neovascularization (CNV) has proven refractory to treatment in most cases. Laser treatment allows removal of CNV and is useful in preserving vision in selected cases that do not involve the central retina, but this is limited to only about 10% of cases. Unfortunately, even if laser photocoagulation is successful, neovascularization recurs in approximately 50-70% of eyes (50% at >3 years and >60% at 5 years) (Macular Photocoagulation Study Group, Arch. Ophthalmol. 204:694-701 (1986)). Furthermore, many patients who develop CNV are not good candidates for laser treatment because the CNV is either too large for laser treatment or difficult to locate, preventing physicians from precisely targeting the laser.

[0007] Retinal neovascularization (RNV) occurs in numerous retinopathies associated with retinal ischemia, such as sickle cell retinopathy, Eales' disease, ocular ischemic syndrome, carotid-cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteriolaritis, radiation retinopathy, retinal vein occlusion, retinal artery occlusion, and retinal embolism. Retinal neovascularization may also occur in inflammatory diseases (birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, toxoplasmosis, and uveitis), choroidal melanoma, chronic retinal detachment, incontinentia pigmenti, and rarely in retinitis pigmentosa.

[0008] A common factor in almost all RNV is retinal ischemia, which releases diffusible angiogenic factors (e.g., VEGF). Neovascularization begins within the retina and then breaches the inner retinal limiting membrane. Neovascularization grows on the posterior surface of the vitreous after the inner retina and vitreous are separated (vitreous detachment). Neovascularization can originate from the optic disc or the surface of the retina. RNV generally progresses to vitreoretinal neovascularization. Iris neovascularization often follows retinal neovascularization. Summary of the Invention [Problem to be solved by the invention]

[0009] Provided herein are methods of treating an ocular disease or disorder in a patient, such as an ocular disease or disorder associated with diabetes. Also provided herein are methods of treating retinopathy of prematurity in a patient. Further provided herein are methods of treating wet age-related macular degeneration in a patient. [Means for solving the problem]

[0010] In one aspect, described herein is a method for treating retinopathy of prematurity by administering a visual cycle modulation (VCM) compound to a patient in need thereof. The methods described herein involve administration of a compound described herein that is a visual cycle modulator (VCM) that reduces or inhibits energy demanding processes in rod photoreceptors. In one embodiment, the VCM compound is administered orally.

[0011] In another aspect, described herein is a method for improving rod-mediated retinal function by administering a VCM compound to a patient with an immature retina. The method described herein reduces rod energy demand in the affected retina, thereby improving rod-mediated retinal function in terms of retinal maturation compared to patients not treated with the drug.

[0012] In another aspect, described herein are methods of modulating the visual cycle by administering a composition comprising a compound described herein to a patient in need thereof, wherein modulation of the visual cycle treats retinopathy of prematurity.

[0013] Further described herein are methods of improving function and / or inhibiting the visual cycle in affected rod cells by contacting the cells with a VCM compound that inhibits the energy demand in the rod cells. In one embodiment of such a method, the treatment is administered locally to the eye. In another embodiment of such a method, the treatment is administered distal to the eye or systemically.

[0014] In one embodiment, a patient being treated with a compound described herein is administered one or more additional compounds or treatments. For example, in one embodiment, a patient is treated with supplemental oxygen.

[0015] In a further embodiment is a method of treating wet age-related macular degeneration in a patient comprising administering to the patient a therapeutically effective amount of a visual cycle modulation (VCM) compound.

[0016] Patients to be treated include humans and non-humans (eg, domestic or wild animals).

[0017] In one embodiment, the composition of the VCM compound is administered orally. The composition can be administered once or multiple times. Administration can be more than once a day, once a day, every other day, every week, or every other month.

[0018] In such methods, treatment ameliorates one or more symptoms in the patient, including, but not limited to, bleeding, leakage, scarring, photoreceptor damage, vision loss, or a combination thereof.

[0019] In one embodiment, a method is described for reducing or inhibiting vascularization (e.g., neovascularization) in a patient, comprising administering to the patient a therapeutically effective amount of a visual cycle modulation (VCM) compound. In one embodiment, the vascularization is associated with choroidal neovascularization. In one embodiment, the vascularization is associated with retinal neovascularization. The inhibition or reduction of vascularization is, for example, at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0020] In one embodiment is a method of treating choroidal neovascularization in a patient comprising administering to the patient a therapeutically effective amount of a visual cycle modulation (VCM) compound.

[0021] One embodiment described herein is a method of protecting the eye during a medical procedure that requires exposure of the eye to bright light, laser light that results in prolonged and / or excessive pupil dilation or otherwise makes the eye sensitive to light, comprising administering a composition comprising a compound described herein to a patient in need thereof. The compounds described herein inhibit the visual cycle by at least 50% at a sufficient dose. Thus, in some embodiments, an effective amount inhibits the visual cycle of the eye of a subject undergoing a medical procedure by at least 50%, at least 75%, or at least 90%. Furthermore, the duration of inhibition is also dose-dependent. Thus, in one embodiment, inhibition continues for at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, or at least 48 hours. Finally, the compounds described herein are reversible inhibitors of the visual cycle, such that the subject's visual cycle returns to normal within 3 half-lives. In one embodiment, the compound used in conjunction with such aforesaid medical procedure is emixustat.

[0022] In another aspect, dosing schedules (e.g., number of doses per day) for treating the eye diseases and conditions described herein are described. In one embodiment, the compound is administered once a day (including multiple sub-doses of the compound administered at about the same time); in another embodiment, the compound is administered once every two days (including multiple sub-doses of the compound administered at about the same time); in yet another embodiment, the compound is administered once every three or more days (including multiple sub-doses of the compound administered at about the same time).

[0023] In another aspect, a dosing schedule (e.g., difference between doses of subsequent administrations) for treating the ocular diseases and conditions described herein is described. In one embodiment, the compound is administered on day 1 at a higher dose level than the dose level administered on subsequent days (e.g., a loading dose). In another embodiment, the compound is administered on day 1 at twice the dose level administered on subsequent days. In another embodiment, the compound is administered on day 1 at three times the dose level administered on subsequent days.

[0024] In another aspect, described herein are dosing schedules (e.g., the time of day when the compound is administered) for treating the ocular diseases and conditions described herein. In one embodiment, the compound is administered in the morning; in another embodiment, the compound is administered in the evening; in another embodiment, the compound is administered upon waking; in another embodiment, the compound is administered before going to bed. In one embodiment, the compound is administered as a controlled release formulation at night. In another embodiment, the compound is administered before, during, or after a meal. In some embodiments, the meal is breakfast; in another embodiment, the meal is lunch; in yet another embodiment, the meal is dinner / supper.

[0025] In one embodiment, the daily dose of (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol is from about 4 mg to about 100 mg. In another embodiment, the daily dose of (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol is about 2 mg; about 5 mg; about 7 mg; about 10 mg; about 15 mg; about 20 mg; about 40 mg; about 60 mg; about 75 mg; or about 100 mg.

[0026] In some embodiments, visual cycle inhibition is measured by ERG. Information regarding dosages of the compounds described herein sufficient to inhibit the visual cycle by at least 50%, and methods for determining visual cycle inhibition in a subject (including ERG), are disclosed in U.S. Patent Application Publication US2011 / 0003895, the contents of which are incorporated herein by reference.

[0027] In one embodiment, the composition is orally administered prior to the medical procedure, hi one embodiment, the composition is administered 24 hours and / or 48 hours after the medical procedure.

[0028] In one embodiment, the composition of the VCM compound is administered orally. The composition can be administered once or multiple times. Administration can be more than once a day, once a day, every other day, every week, or every other month.

[0029] In such methods, treatment ameliorates one or more symptoms in the patient, including, but not limited to, defects in Bruch's membrane, increased amounts of vascular endothelial growth factor (VEGF) in the eye, myopia, myopic degeneration, deterioration of central vision, metamorphopsia, color vision disorders, vascular bleeding, or a combination thereof.

[0030] In one embodiment is a method of treating retinal neovascularization in a patient comprising administering to the patient a therapeutically effective amount of a visual cycle modulation (VCM) compound.

[0031] In one embodiment, the retinal neovascularization is associated with one or more retinopathies, including, but not limited to, sickle cell retinopathy, Eales' disease, ocular ischemic syndrome, carotid-cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteriolar inflammation, radiation retinopathy, retinal vein occlusion, retinal artery occlusion, retinal embolism, birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, toxoplasmosis, uveitis, choroidal melanoma, chronic retinal detachment, incontinentia pigmenti, and retinitis pigmentosa.

[0032] In another aspect, a method of treating an eye disease or disorder associated with diabetes in a patient; a method of treating or preventing retinopathy of prematurity in a patient; or a method of treating an eye disease or disorder associated with ocular neovascularization in a patient, comprising administering to a patient a compound of formula (A) or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof: [ka] [In the formula, X is -C(R 9 )=C(R 9 )-, -C≡C-, -C(R 9 )2-O-, -C(R 9 )2-C(R 9 )2-, -C(R 9 )2-S-, -C(R 9 )2-S(O)2-, or -C(R 9 )2-NR 9 - selected from Y is a) substituted or unsubstituted carbocyclyl, optionally substituted with C1-C4 alkyl, halogen, -OH or C1-C4 alkoxy; b) substituted or unsubstituted carbocyclylalkyl, optionally substituted with C1-C4 alkyl, halogen, -OH or C1-C4 alkoxy; c) a substituted or unsubstituted aralkyl, optionally substituted with C1-C4 alkyl, halogen, -OH, or C1-C4 alkoxy; or d) Substituted or unsubstituted C3-C, optionally substituted with halogen, -OH, or C1-C4 alkoxy. 10 Alkyl is selected from R 1 is hydrogen and R 2 is hydroxyl, or R 1 and R 2 forms an oxo, R 7 is hydrogen, R 8 is hydrogen or CH3, R 9 each independently represents hydrogen or a substituted or unsubstituted C1-C4 alkyl; R 33 are each independently selected from halogen, or substituted or unsubstituted C1-C4 alkyl, and n is 0, 1, 2, 3, or 4. The method comprises administering to the patient a therapeutically effective amount of a composition comprising:

[0033] Another embodiment provides a method of treating a diabetes-associated eye disease or disorder in a patient; a method of treating or preventing retinopathy of prematurity in a patient; or a method of treating an eye disease or disorder associated with ocular neovascularization in a patient, wherein n is 0, 1, or 2.

[0034] Another embodiment is where X is -C(R 9 )=C(R 9 Another embodiment provides a method where X is -C≡C-. Another embodiment provides a method where X is -C(R 9 )2-O-. Another embodiment provides a method in which X is -C(R 9 )2-C(R 9 )2-. Another embodiment provides a method in which X is -C(R 9 )2-S-. Another embodiment provides a method in which X is -C(R 9 )2-S(O)2-. Another embodiment provides a method in which X is -C(R 9 )2-NR 9-Provides a method for

[0035] Another embodiment is where Y is a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted C-C 10 Another embodiment provides a method where Y is alkyl. Another embodiment provides a method where Y is substituted or unsubstituted carbocyclyl. Another embodiment provides a method where the substituted or unsubstituted carbocyclyl is a substituted or unsubstituted 4-, 5-, 6- or 7-membered ring. Another embodiment provides a method where the substituted or unsubstituted carbocyclyl is a 6-membered ring. Another embodiment provides a method where the substituted or unsubstituted 6-membered ring is substituted or unsubstituted cyclohexyl. Another embodiment provides a method where the substituted or unsubstituted 6-membered ring is substituted or unsubstituted cyclohexyl and X is -C(R 9 ) 2-O-.

[0036] In another embodiment, Y is a substituted or unsubstituted C 10 Another embodiment is a substituted or unsubstituted C3-C alkyl. 10 The method is provided wherein the alkyl is a substituted or unsubstituted C3-C6 alkyl. Another embodiment provides a method wherein the substituted C3-C6 alkyl is substituted with a C1-C2 alkoxy group. Another embodiment provides a method wherein the substituted C3-C6 alkyl is -CH2CH2CH2OCH3.

[0037] Another embodiment is R 1 is hydrogen and R 2 Another embodiment provides a method in which R 1 and R 2 Another embodiment provides a method in which R 8 Another embodiment provides a method in which R 8 Another embodiment provides a method in which R 1 is hydrogen and R 2 is hydroxyl and X is -C(R 9 ) 2-O-.

[0038] One embodiment is a method of treating a diabetes-related ocular disease or disorder in a patient; treating or preventing retinopathy of prematurity in a patient; or treating an ocular disease or disorder associated with ocular neovascularization in a patient, comprising: [ka] [ka] or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof.

[0039] Another embodiment is a composition comprising: [ka] or a stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof.

[0040] Another embodiment is a composition comprising: [ka] or a stereoisomer, N-oxide or pharma- ceutical acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an ocular disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0041] Another embodiment is a composition comprising: [ka] or a tautomer, stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an ocular disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0042] Another embodiment is a composition comprising: [ka] or a stereoisomer, N-oxide or pharma- ceutical acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an ocular disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0043] Another embodiment is a composition comprising: [ka] or a tautomer, stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an ocular disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0044] Another embodiment is a composition comprising: [ka] or a tautomer, stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an ocular disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0045] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0046] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0047] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0048] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0049] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0050] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0051] Another embodiment is a composition having the structure: [ka] or a stereoisomer, N-oxide, or pharma- ceutically acceptable salt thereof; a method for treating or preventing retinopathy of prematurity in a patient; or a method for treating an eye disease or disorder associated with ocular neovascularization in a patient, the method comprising the steps of:

[0052] Another embodiment provides a method of treating an eye disease or disorder associated with diabetes in a patient; a method of treating or preventing premature retinopathy in a patient; or a method of treating an eye disease or disorder associated with ocular neovascularization in a patient, in which the composition is administered orally to the patient. Another embodiment provides a method of treating an eye disease or disorder associated with diabetes in a patient; a method of treating or preventing premature retinopathy in a patient; or a method of treating an eye disease or disorder associated with ocular neovascularization in a patient, in which the composition is administered once a day. Another embodiment provides a method of treating an eye disease or disorder associated with diabetes in a patient; a method of treating or preventing premature retinopathy in a patient; or a method of treating an eye disease or disorder associated with ocular neovascularization in a patient, in which the treatment improves the patient's central vision.

[0053] Further embodiments provide a method of treating a diabetes-associated eye disease or disorder in a patient, further comprising administering one or more additional therapeutic regimens; treating or preventing retinopathy of prematurity in a patient; or treating an eye disease or disorder associated with ocular neovascularization in a patient. Another embodiment provides a method of treating an ocular disease or disorder associated with diabetes in a patient; a method of treating or preventing retinopathy of prematurity in a patient; or a method of treating an ocular disease or disorder associated with ocular neovascularization in a patient, wherein the one or more treatment regimens are laser treatment, cryotherapy, fluorescein angiography, vitrectomy, corticosteroids, anti-vascular endothelial growth factor (VEGF) treatment, vitrectomy for persistent diffuse diabetic macular edema, pharmacological vitreolysis in the management of diabetic retinopathy, fibrates, renin-angiotensin system (ras) blockers, peroxisome proliferator-activated receptor gamma agonists, anti-protein kinase C (PKC), islet cell transplantation, therapeutic oligonucleotides, growth hormone and insulin growth factor (IGF), control of systemic factors, or combinations thereof.

[0054] Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is diabetic retinopathy. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is non-proliferative diabetic retinopathy. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is proliferative diabetic retinopathy. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is diabetic maculopathy. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is diabetic macular edema. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is neovascular glaucoma. Another embodiment provides a method of treating a diabetes-related eye disease or disorder in a patient, wherein the diabetes-related eye disease or disorder is macular ischemia. Incorporation by Reference

[0055] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0056] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief description of the drawings]

[0057] [Figure 1] 1 is a graph showing a timeline for groups 1 to 3 described in Example 3.

[0058] [Diagram 2]1 is a graph showing a timeline for the four groups described in Example 3.

[0059] [Diagram 3] 1 is a graph showing a timeline for groups 5 and 6 described in Example 3.

[0060] [Figure 4A] FIG. 1 illustrates the visual cycle, showing the biochemical transformation of visually active retinoids in the retina. [Figure 4B] FIG. 1 illustrates a possible means of action of ACU-4429.

[0061] [Diagram 5] Graph showing mean oral pharmacokinetic (PK) profile data for ACU-4429 Phase 1a.

[0062] [Figure 6] 1 is a graph showing ACU-4429 Phase 1a rod ERG suppression.

[0063] [Figure 7] 13 is a graph showing PK data from Phase 1b.

[0064] [Figure 8] FIG. 1 shows a timeline for an experiment to test whether ACU-4935 reduced VEGF upregulation caused by hypoxic conditions.

[0065] [Figure 9] FIG. 1 is a graph showing VEGF protein expression caused by hypoxic conditions following treatment with ACU-4935.

[0066] [Figure 10] FIG. 1 is a graph showing VEGF mRNA levels caused by hypoxic conditions following treatment with ACU-4935.

[0067] [Figure 11A] Mean concentration versus time profile for blood or plasma. [Figure 11B] Average concentration versus time profiles in ocular tissues.

[0068] [Figure 12] Figure 12A: Metabolite radioactivity profile 4 hours after dosing on day 7 as described in Example 10. Figure 12A: G4M plasma results at 4 hours on day 8. Figure 12B: G3M retinal pigment epithelium results at 4 hours.

[0069] [Figure 13] 1 is a graph showing the average cumulative percentage of radioactive dose recovered as described in Example 10.

[0070] [Figure 14] FIG. 1 shows that visual cycle modulators (VCMs), such as ACU-4420 and ACU-4935, inhibit visual cycle isomerases, thereby mimicking the conditions that result in phototransduction and reducing dark current.

[0071] [Figure 15] FIG. 1 shows the protocol for treatment of 129 SvE pups (PO) with ACU-4420 and ACU-4935.

[0072] FIG. 16 shows that VCM inhibits angiogenesis. [Figure 16A] FIG. 1 shows isolectin staining of a retinal flat mount preparation, with areas of neovascularization outlined in red. [Figure 16B] 1 is a histogram comparing the % angiogenesis in the various treatment groups. [Figure 16C]Figure 1 shows that ACU-4429 inhibited angiogenesis and 11-cis-RAL in a dose-dependent manner. Figure 1 shows that ACU-4429 reduced intraocular 11-cis-RAL concentrations and thus reduced visual cycle isomerase activity in a dose-dependent manner (ED50 0.88 mg / kg). The difference between ACU-4429 and vehicle was statistically significant (P<0.01). [Figure 16D] Figure 1 shows that ACU-4429 inhibited angiogenesis and 11-cis-RAL in a dose-dependent manner. Figure 1 shows that ACU-4429 reduced intraocular 11-cis-RAL concentrations and thus reduced visual cycle isomerase activity in a dose-dependent manner (ED50 0.88 mg / kg). The difference between ACU-4429 and vehicle was statistically significant (P<0.01). [Figure 16E] Figure 1 shows that ACU-4429 dose-dependently inhibited angiogenesis and 11-cis-RAL. Figure 1 shows that angiogenesis in the left eye (measured by isolectin-stained flat-mount preparations) was dose-dependently reduced by ACU-4429. This reduction was significant at 3.0 mg / kg and 10.0 mg / kg by one-way ANOVA comparison of vehicle (water) in 21% O2, vehicle (water) in 75% O2, and ACU-4429 treatment. [Figure 16F] Figure 1 shows that ACU-4429 dose-dependently inhibited angiogenesis and 11-cis-RAL. Figure 1 shows that angiogenesis in the left eye (measured by isolectin-stained flat-mount preparations) was dose-dependently reduced by ACU-4429. This reduction was significant at 3.0 mg / kg and 10.0 mg / kg by one-way ANOVA comparison of vehicle (water) in 21% O2, vehicle (water) in 75% O2, and ACU-4429 treatment.

[0073] [Figure 17]Diagram of the neural retina and its vascular supply (not to scale). Showing the layers of the neural retina (ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer). Blood flow is rapid through the choroidal vessels. The retinal vasculature, visible by ophthalmoscopy, is located in the ganglion cells on the vitreous surface of the retina and extends deep into a capillary network posterior to the receptor layer. Retinal arteriole diameter adjusts to fluctuations in blood oxygen concentration ("autoregulation").

[0074] [Figure 18] FIG. 1 shows a logistic growth curve showing human rhodopsin content as a function of age (Fulton et al., Invest. Ophthalmol. Vis. Sci., (1999) 40: 1878-1883). Arrows indicate age of ROP onset in preterm infants (Palmer et al. Ophthalmology, (1991) 98:1628-1640).

[0075] [Figure 19] A rat model of prematurity retinopathy. (a) Scanning laser ophthalmoscopy (SLO) images obtained using blue (488 nm) laser stimulation (Seeliger et al., Vision Res., (2005) 45: 3512-9) after fluorescein injection in 22-day-old control and ROP rats. (Pigmented rats are used to facilitate SLO imaging). The integrated curvature of each retinal arteriole is expressed as a percentage of the average in controls (ICA). High ICA values ​​for ROP rats reflect greater vascular tortuosity in those arterioles. Choroidal appearance is similar in control and ROP funduses. (b) Sample electroretinogram (ERG) responses to full-field stimulation in control and ROP rats. Both rats are tested with the same flash intensity as indicated. The vertical grey line indicates the time when the flash appears.

[0076] [Figure 20]Characterization of the experimental paradigm. Ambient oxygen and photoperiod were tightly regulated and synchronized. VCM administration was designed to target the rapid growth phase of intraretinal rhodopsin developmental expansion (arrows). The areas within the dashed boxes indicate the three test windows.

[0077] [Figure 21] Figure 1 shows photographs of H&E staining of paraffin sections (obtained from Example 7, Chronic Light Induces CNV). The outer nuclear layer is thinnest in sections obtained from eyes of light and vehicle treated animals.

[0078] [Figure 22] 1 is a graph showing the number of nuclear rows in the outer nuclear layer of H&E sections from animals treated with vehicle or ACU-4429 at ambient light and 3000 lux. Data are means±SEM.

[0079] [Diagram 23] FIG. 13 is a graph showing the number of blood vessels crossing layers / compartments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] The present disclosure relates to a method of treating diabetic retinopathy. As used herein, "diabetic retinopathy" refers to the degeneration of the retina due to microvascular degeneration seen in diabetes. Blood vessels that supply oxygen to the retina of the eye are damaged by prolonged high levels of blood glucose (hyperglycemia). The disease generally progresses slowly over a period of months. However, over time, diabetic retinopathy can become more severe and cause vision loss. Diabetic retinopathy usually affects both eyes. Diabetic retinopathy progresses from mild non-proliferative abnormalities characterized by increased vascular permeability, to moderate and severe non-proliferative diabetic retinopathy (NPDR) characterized by vascular occlusion, to proliferative diabetic retinopathy (PDR) characterized by new vascular proliferation on the posterior surface of the retina and vitreous. Macular edema, characterized by retinal thickening from leaking blood vessels, can develop at all stages of retinopathy. Additionally, conditions such as pregnancy, puberty, glycemic control, hypertension, and cataract surgery can accelerate these degenerations.

[0081] Nonproliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic maculopathy are the three main types of diabetic retinopathy.

[0082] Nonproliferative diabetic retinopathy (NPDR) is considered the early stage of retinopathy and is the most common one seen in diabetic patients. The capillaries of the retina are only mildly affected, but bulges (microaneurysms) and interconnections (microvascular abnormalities in the retina) may form and / or fluid (edema), protein deposits (exudation) and blood (hemorrhage) may leak. Another typical sign of nonproliferative diabetic retinopathy (NPDR) is the presence of bulging white spots on the retina (cotton-wool spots). These degenerations can occur anywhere throughout the retina, including the macula.

[0083] There are three stages of nonproliferative diabetic retinopathy:

[0084] (1) Mild nonproliferative diabetic retinopathy: In this early stage, at least one microaneurysm may develop, which is a small, balloon-like area of ​​bulging retinal blood vessels.

[0085] (2) Moderate nonproliferative diabetic retinopathy: As the disease progresses, some of the blood vessels that supply nourishment to the retina become blocked.

[0086] (3) Severe nonproliferative diabetic retinopathy: Many more blood vessels become blocked, cutting off the blood supply to areas of the retina that send signals to the body to grow new blood vessels to supply them with nutrients.

[0087] Nonproliferative diabetic retinopathy does not cause any problems to patients, as vision remains normal as long as the macula is not affected. However, because the symptoms of diabetic retinopathy are generally not visible at this stage, it is recommended that regular retinal screening eye examinations should be performed to monitor for signs of progression to more severe stages of retinopathy.

[0088] Proliferative Diabetic Retinopathy (PDR): This stage comes after severe non-proliferative diabetic retinopathy and is characterized by the growth of abnormal new blood vessels in the eye. When diabetes causes blood vessel blockage, parts of the eye and retina become starved of oxygen and nutrients, resulting in ischemia. The eye tries to respond to this condition by developing a new blood supply to the oxygen-starved areas. Unfortunately, fragile new blood vessels that bleed easily form instead. This process is called neovascularization. These abnormal new blood vessels grow in inappropriate places on the retinal surface and within the vitreous gel. When these new blood vessels bleed into the vitreous cavity, a vitreous hemorrhage occurs. This blood blocks light entering the eye from reaching the retina. The degree of vision loss can range from mild to severe, depending on how much blood is in the eye. Vision can slowly improve as the hemorrhage gradually clears over a period of months.

[0089] The abnormalities in neovascularization can also result in the formation of scar tissue that pulls on the retina, causing tractional retinal detachment. Retinal detachment can affect any part of the retina. If the retinal detachment affects the macula, the patient may lose their central vision, and it can only be treated by surgery.

[0090] Diabetic maculopathy: Diabetic maculopathy is the most common cause of vision loss in diabetes. It occurs when the macula becomes affected by retinopathy degeneration caused by diabetes. The macula is located in the center of the retina and is important for central vision and for seeing details clearly. Thus, central vision and ability to see details are affected in patients who develop diabetic maculopathy. For example, affected individuals may find it difficult to recognize faces in the distance or read small print. The degree of vision loss can range from mild to severe. However, even in the worst cases, peripheral vision (side vision), which allows an individual to move around the home and outside, remains unaffected.

[0091] Diabetic retinopathy (DR) is an eye disorder characterized by excessive blood vessel formation that develops in diabetes due to thickening of the capillary basement membrane and lack of contact between the pericytes and endothelial cells of the capillaries. Loss of pericytes increases capillary leakage and disrupts the blood-retinal barrier. Diabetic retinopathy is the result of retinal microvascular degeneration. Hyperglycemia-induced pericyte death and thickening of the basement membrane result in failure of the blood vessel walls. These lesions alter the formation of the blood-retinal barrier and make the retinal vessels more permeable. Microvessels - for example, those in the eye - are highly susceptible to hypoglycemia (blood glucose) control. Excessive retention of glucose and / or fructose damages the retinal capillaries. Macular edema can also develop if the damaged vessels leak fluid and lipids onto the macula. These fluids cause macular swelling and blurred vision. This damage also causes oxygen deprivation in the retina.

[0092] As the disease progresses, lack of oxygen in the retina stimulates the formation of blood vessels along the retina and in the vitreous humor, a clear gel that fills the interior of the eye. Without timely treatment, these new blood vessels can cause bleeding, blurred vision, and destruction of the retina. Fibrovascular proliferation can also cause tractional retinal detachment. New blood vessels can also grow into the anterior chamber angle, causing neovascular glaucoma.

[0093] Vision loss due to diabetic maculopathy occurs in two ways.

[0094] Diabetic macular edema (DME) is a swelling and thickening of the macula. It is caused by leakage of fluid from the retinal blood vessels in the macula. Vision becomes blurred because the structure and function of the photoreceptor cells in the macula are destroyed. Vision loss due to macular edema can be corrected using lasers and injections into the eye.

[0095] Macular ischemia occurs when the tiny retinal blood vessels (capillaries) to the macula become blocked. Because the macula does not receive enough blood supply to function properly, vision becomes blurred. Unfortunately, there is no effective treatment for macular ischemia. Macular edema is due to fluid leaking from retinal blood vessels. Hard exudates are yellowish deposits found in the retina. Hard exudates are caused by protein leakage.

[0096] The following conditions are some of the possible causes of diabetic retinopathy:

[0097] Diabetes: Sustained hyperglycemia (high blood glucose levels) affects the organization and function of retinal capillaries. Excess glucose, when diverted to alternative metabolic pathways, is converted to sorbitol. Sorbitol causes the death or dysfunction of retinal capillary pericytes. This leads to weakening of capillary walls that can lead to the formation of microaneurysms, the earliest sign of diabetic retinopathy. Weakened capillary walls also increase permeability and can lead to exudates. The increased tendency for platelet aggregation and adhesion (clot formation) as a result of diabetes causes capillary circulation to become stagnant or completely impaired by obstruction. This can also contribute to the development of diabetic retinopathy.

[0098] Type 1 and Type 2 Diabetes: Individuals diagnosed with type 1 diabetes are considered insulin-dependent because they require injections or other medications to provide the insulin that the body cannot produce on its own. Due to the lack of insulin, blood sugar is uncontrolled and blood glucose levels are very high. Individuals with type 2 diabetes are considered to be insulin-independent or insulin-resistant. Individuals with this type of diabetes produce enough insulin, but the body is unable to properly utilize it. The body then compensates by producing more insulin, which can cause an accompanying abnormal rise in blood sugar levels. People with type I diabetes (juvenile onset) and type II diabetes (adult onset) are all at risk for developing diabetic retinopathy. However, people with type 1 diabetes appear to be more likely to develop retinopathy than those with type 2 diabetes.

[0099] Type 1 and Type 2 Diabetes: People with type 1 and type 2 diabetes are at increased risk of developing diabetic retinopathy.

[0100] Excessive alcohol: Excessive alcohol intake decreases vitamin B12 and thiamine levels, but alcohol consumption itself has not been linked to diabetic retinopathy, consuming empty calories from alcohol can make adherence to a calorie-restricted diabetic diet very difficult, and the effect of moderate alcohol on retinopathy is unclear.

[0101] Hypertension and other vascular risk factors, such as obesity and dyslipidemia, may influence the development and progression of retinopathy.

[0102] High cholesterol: Cholesterol can worsen retinopathy by hardening the large blood vessels and cause damage to the small blood vessels of the eye.

[0103] Renal disease, as evidenced by proteinuria and elevated urea / creatinine levels, is a good predictor of the presence of retinopathy.

[0104] Pregnancy: Pregnancy may worsen existing retinopathy but is probably not a direct cause. Women with diabetes are at slightly higher risk during pregnancy. All pregnant women with diabetes are recommended to have detailed eye examinations every three months to protect their vision.

[0105] Kidney damage: Associated with diabetic retinopathy, but diabetic retinopathy appears to induce kidney damage rather than the other way around.

[0106] Chromosome 15q deletion: a rare chromosomal abnormality involving the deletion of genetic material from the long arm of chromosome 15.

[0107] It is believed that intraocular surgery may, in some cases, increase the risk of progression of diabetic retinopathy.

[0108] The early stages of non-proliferative diabetic retinopathy often have no symptoms. Signs and symptoms of diabetic retinopathy generally appear as the disease progresses toward progressive or proliferative diabetic retinopathy. Signs that diagnose diabetic retinopathy include one or more of the following: degeneration of blood vessels; swelling of the retina (macular edema); pale deposits on the retina; damage to nerve tissue; visual appearance of vascular leakage; loss of central or peripheral vision; temporary or permanent decrease in vision; development of dark spots or shadows in the visual field; spots, blurring, cloudiness or double vision; eye pain; near vision problems unrelated to presbyopia; spots or dark threads (floats) in the visual field; impaired color vision; decreased visual acuity; dark areas or areas of difficulty in the central visual field; deterioration or loss of night vision; enlarged veins and intraretinal microvascular abnormalities; in advanced stages of retinopathy, proliferation of capillaries along the retina and in the clear, gel-like vitreous humor that fills the interior of the eye; nerve damage affecting the eye muscles that control eye movement (neuropathy); involuntary eye movements (nystagmus); fluctuating and progressive worsening of vision; macular edema; macular ischemia; traction retinal detachment; sudden, severe, painless loss of vision; increased vascular permeability leading to edema; endothelial cell proliferation; light flashes (photopsia) or visual field defects; presence of abnormal blood vessels on the iris (rubeosis or nvi), cataracts (associated with diabetes), and vitreous cells (blood in the vitreous or pigmented cells if there is a retinal detachment with holes formed); microaneurysms - physical weakening of the capillary walls that make them more susceptible to leakage; hard exudates - lipoprotein / other protein clots leaking from retinal vessels; hemorrhages - breakdown of weakened capillaries that appear as small specks / large blemishes or "frame" hemorrhages along nerve fiber bundles in the superficial retinal layers (bleeding originates from larger, more superficial arterioles); cotton wool spots - accumulation of axonal debris due to metabolic insufficiency of axons at the periphery of an ischemic infarct; and neovascularization - attempts (by remaining healthy retina) to revascularize hypoxic retinal tissue.

[0109] The present disclosure also relates to the use of visual cycle modulation (VCM) compounds for the treatment of retinopathy of prematurity (ROP). The present disclosure provides the first evidence of the efficacy of systemic treatment with non-retinoid VCM in retinopathy of prematurity. One of the key factors in this process is high O2 content, which is important when the subject is a newborn. Premature infants are placed in a high oxygen atmosphere to support immature lung function, but in this case, high oxygen concentration suppresses the normal development of retinal vasculature. When the infant is returned to normal air, the retina becomes ischemic under the developed vasculature. This ischemia induces VEGF expression and angiogenesis. See, for example, FIG. 4B. VCM works by increasing apo-rhodopsin, which reduces dark current and therefore oxygen consumption.

[0110] Described herein are VCM compounds for treating or preventing retinal diseases or disorders, particularly those related to or involving vascular abnormalities, such as ROP. The methods described herein involve the administration of VCM compounds that modulate the visual cycle.

[0111] As a system, the mammalian retina is susceptible to diseases that affect the balanced interconnection of the neural retina and the vasculature that nourishes it; when this balance is disrupted, vision impairment results. Diseases such as photoreceptor degeneration that primarily affect the neural retina also affect the retinal vasculature. Diseases clinically characterized by abnormalities in the choroidal or retinal vasculature, such as ROP, also affect retinal neurons. All of these conditions are associated with hypoxic-ischemic disorders of neural tissue. Photoreceptors are specialized cells with the highest oxygen demands of any cell in the body (Steinberg, R., Invest. Ophthalmol. Vis. Sci., (1987) 28: 1888-1903), and play a role in all hypoxic-ischemic disorders of the retina.

[0112] In normal development, as rod photoreceptors differentiate and begin to produce rhodopsin (the molecule responsible for capturing light), their extremely high oxygen demand renders the retina hypoxic and activates the proliferation of retinal blood vessels. However, in ROP, supplemental oxygen administered to emergency cardiopulmonary care of premature infants renders the retina hyperoxic, disrupts normal vascular proliferation, and leaves the peripheral retinal vessels avascular. When supplemental oxygen is stopped, the peripheral retina becomes hypoxic. Hypoxia triggers a molecular cascade that results in the formation of abnormal retinal blood vessels, which are used clinically in the diagnosis of ROP. Even if premature infants are exposed to high ambient oxygen, immature lungs and other medical complications often result in fluctuations in blood oxygen, thus resulting in the development of both retinal hypoxia and hyperoxia that affect the photoreceptors. The developing neural retina and its vasculature are under coordinated molecular control, and the vascular abnormalities of ROP are related to neural retinal function. Recent studies have confirmed that the degree of rod dysfunction in ROP is predictive of the degree of abnormalities observed in the retinal vasculature, but the degree of abnormalities observed in the retinal vasculature may not be predictive of the degree of rod dysfunction in ROP.

[0113] As used herein, "immature retina" refers to a retina similar in morphology / function to that of a preterm infant or a retina born before term. Immature retina can be characterized by the presence of underdeveloped or disorganized blood vessels, regardless of the presence of scar tissue. Generally, a premature human infant is an infant born at or before 37 weeks of gestation. Conversely, the term "mature retina" refers to a retina similar in morphology / function to that of a full-term infant or a full-term infant.

[0114] As used herein, the phrase "reducing rod energy demand" or "inhibiting rod energy demand" refers to a reduction in the oxygen demand of rod cells by at least 10%; preferably, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more. In general, it is preferred that the oxygen demand of rod cells be maintained below the level required to induce pathological angiogenesis (i.e., blood vessel proliferation) or vascular abnormalities.

[0115] The term "vascular abnormality" is used herein to mean an abnormal or pathological level of vascular growth (e.g., angiogenesis) or morphology (e.g., vascular tortuosity) of blood vessels that prevents the retina from properly developing to the "mature retina" as that term is used herein. One skilled in the art can set the amount of agent administered or the timing of administration to maintain vascular growth and morphology below that of pathological vascular growth as assessed, for example, by laser Doppler blood flow analysis. In an alternative embodiment, the level of retinal vascular tortuosity is used to assess the degree of pathological vascular morphology and / or growth. Methods for measuring vascular tortuosity are further described herein.

[0116] As used herein, the term "supplemental oxygen" refers to a concentration of oxygen that exceeds the atmospheric oxygen concentration required to maintain a subject's blood oxygen concentration at a desired concentration (i.e., about 20-21%). Typically, supplemental oxygen is provided in a clinical setting to maintain a blood oxygen concentration of 100%, as assessed, for example, using transcutaneous oxygen monitoring. Monitoring blood oxygen concentration and modifying the concentration of "supplemental oxygen" to maintain, for example, 100% blood oxygen concentration is standard procedure in clinical settings (e.g., neonatal intensive care units) and is well known to those of ordinary skill in the medical arts.

[0117] Retinal vascular and neurological disorders Despite advances in the medical management of retinal neovascular diseases, such as retinopathy of prematurity (ROP), retinal neurovascular disease remains the leading cause of blindness worldwide.

[0118] For ROP, current treatments include photocoagulation of the surrounding vasculature, which has its own negative effects, and experimental approaches such as treatment with antiangiogenic drugs, whose efficacy is unknown. Rod photoreceptors are unique to the eye and have the highest oxygen demand of any cell in the body, and therefore may be involved in hypoxic-ischemic neovascular retinopathy (Arden et al., Br J Ophthalmol (2005) 89:764; and Fulton et al., Doc Ophthalmol, (2009) 118(1):55-61). The ROP rat model provides an in vivo system in which the relationship of photoreceptors to the retinal vasculature can be studied and manipulated.

[0119] Abnormalities in retinal function are a hallmark of neovascular retinopathy (Fulton et al., Doc Ophthalmol, (2009) 118(1):55-61). Visual loss in neovascular retinopathy is due to vascular abnormalities, and the severity of lifelong retinal dysfunction that persists after resolution of vascular abnormalities is related to the severity of the preceding vascular disease (Fulton et al., Arch Ophthalmol (2001) 119:499). However, data from the ROP rat model indicate that rod photoreceptor dysfunction precedes the vascular abnormalities that traditionally define ROP and predict their severity (Reynaud, and Dorey, Invest Ophthalmol Vis Sci (1994) 35:3169; Akula, Invest Ophthalmol Vis Sci (2007) 48: 4351). Vascular morphological abnormalities are the primary diagnostic criterion for ROP; however, ROP is primarily a neuroretinal disorder due to secondary vascular abnormalities. The appearance of vascular abnormalities characteristic of acute ROP coincides with an elongation of rod photoreceptor outer segment development and a concomitant increase in retinal content of rhodopsin (Lutty et al., Mol Vis (2006) 12: 532; and Dembinska et al., Invest Ophthalmol Vis Sci (2002) 43:2481).

[0120] Rod cell physiology and metabolism Rods perform three combined metabolically demanding processes: dark current generation, visual pigment maintenance (visual cycle), and outer segment turnover, all of which occur concomitantly with the developmental elongation of rod outer segments (ROS) and an increase in the rhodopsin content of the eye. The mechanism of rod signaling is physiologically unique. In the dark, sodium and other cations imported through cyclic guanosine monophosphate (cGMP)-gated channels in the ROS are pumped out by pumps in the rod inner segment (RIS) and rapidly recycled in a volume equal to the entire cytosol every 30 seconds (Hagins, et al., Proc Natl Acad Sci USA (1989) 86:1224). After a light flash, a molecular cascade initiated by photon capture by rhodopsin and resulting in the depletion of cGMP reduces the dark current according to a delayed Gaussian model that can be described by an intrinsic amplification constant, A (Lamb and E Pugh, J Physiol (1992) 449:719; and Pugh and Lamb, Biochem Biophys Acta (1993) 1141:111).

[0121] After photon capture, the chromophore (retinol) of rhodopsin is isomerized, which releases retinol from opsin and initiates phototransduction. The chromophore is transferred from ROS to the retinal pigment epithelium (RPE), where it undergoes a series of transformations before being transferred back to ROS via the apical process of the RPE as retinol. There, it covalently binds to its active site lysine in opsin, reverting to rhodopsin and completing the visual cycle (RR Rando, Chem Rev (2001) 101:1881). The rate-limiting step of the visual cycle is mediated by the isomerohydrolase enzyme complex, RPE65 (Moiseyev et al., Proc Natl Acad Sci USA (2005) 102:12413). Other by-products of phototransduction in ROS are released by the circadian elimination process of ROS tips; each RPE cell phagocytose thousands of disks shed from 30-50 embedded rods each day (RW Young, J Cell Biol (1967) 33:61). Controlled downregulation of the visual cycle by targeted inhibition of RPE65 activity reduces the efflux of retinoids by the ROS / RPE complex; this would render rods more resistant to damage caused by hyperoxia and hypoxia by reducing their metabolic demand (Wellard et al., Vis Neurosci (2005) 22:501). This would also slow phagocytic activity, which could result in elongation of rod outer segments.

[0122] Translating animal models to patients Photoreceptors are closely located in the choroidal vasculature. Highly organized post-receptor retinal neurons form a layer that is supplied by the retinal blood vessels. Although the choroid is the main supply to the photoreceptors, photoreceptor degeneration is nevertheless associated with weakening of the retinal arterioles (Hansen et al., Vision Research, 48(3):325-31 (2008)). Without wishing to be bound by theory, it is presumed that because the photoreceptor layer is such an abnormal oxygen sink, as the photoreceptors degenerate, their metabolic demand is reduced and the retinal vasculature is weakened due to the always low oxygen demand of the neural retina (Hansen et al., Vision Research, 48(3):325-31 (2008)).

[0123] Intimate connections between photoreceptors and the retinal vascular network are evident in the developing retina. Postreceptor cells differentiate into photoreceptors, which are the final retinal cells to mature. When rod outer segment formation proceeds to the posterior peripheral gradient, a vascular covering also occurs. This simultaneous and coordinated development of neural and vascular components is characteristic of normal retinal maturation. In preterm infants, the age of onset of ROP occurs around the time of the rapid developmental increase in rod outer segment length and the resulting increase in rhodopsin content. In addition to immature photoreceptors and retinal vasculature, preterm infants have immature lungs that result in unstable respiratory conditions with the attendant risk of hypoxic injury to immature cells. Clinically, this can be reversed by administering supplemental oxygen, but hyper- and hypoxic concentrations are known to damage immature photoreceptors (Fulton et al. Invest. Ophthalmol. Vis. Sci., (1999) 40: 168-174; and Wellard et al., Vis. Neurosci., (2005) 22: 501-507).

[0124] The rat model of ROP is induced by rearing rat pups in an environment with alternating periods of relatively high and low oxygen during the critical period of rod outer segment outgrowth (Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9; Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 5788-97; Dembinska et al., Invest. Ophthalmol. Vis. Sci., (2001) 42: 1111-1118; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 5447-52; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 2639-47; Penn et al., Invest. Ophthalmol. Vis. Sci., 1995. 36: 2063-2070). After induction, there are abnormalities in the structure and function of the neural retina, resulting in abnormalities in the retinal vasculature (Fulton et al. Invest. Ophthalmol. Vis. Sci., (1999) 40: 168-174; Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9; Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 5788-97; Dembinska et al, Invest. Ophthalmol. Vis. Sci., (2001) 42: 1111-1118; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 5447-52; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 2639-47; Reynaud et al., Invest. Ophthalmol. Vis. Sci., (1995) 36:2071-2079).The morphological abnormalities of the retinal vasculature and the functional abnormalities of the neural retina in ROP rats are similar to those observed in pediatric ROP patients (Dembinska et al., Invest. Ophthalmol. Vis. Sci., (2001) 42: 1111-1118; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 5447-52; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 2639-47; Reynaud et al., Invest. Ophthalmol. Vis. Sci., (1995) 36:2071-2079; Barnaby, AM, Invest. Ophthalmol. Vis. Sci., (2007). 48:4854-60; Fulton et al., Arch. Ophthalmol., (2001)119: 499-505; Gelman, R., Invest. Ophthalmol. Vis. Sci., (2005) 46(12): 4734-4738; Moskowitz et al., Optometry & Vision Science, (2005) 82: 307-317; Fulton, AB, Invest. Ophthalmol. Vis. Sci., 49(2):814-9 (20089). Thus, it is possible to extrapolate the rat model to human treatment.

[0125] The albino rat model of ROP is used to study the neural and vascular properties of the developing retina (Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9; Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 5788-97; Liu, K., Invest. Ophthalmol. Vis. Sci., (2006) 47: 5447-52; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 2639-47). Different schedules of oxygen exposure induce a range of effects on the retinal vasculature, and neural retina has been identified in human ROP cases that model the full range of retinopathy from mild to severe. Oxygen exposure is timed to have an effect on the retina during the ages when rod outer segments are elongating and retinal rhodopsin content is increasing. Longitudinal measurements of electroretinogram (ERG) responses and retinal vascular characteristics are obtained in infant (approximately 20 days of age), juvenile (approximately 30 days of age), and adult (approximately 60 days of age) rats.

[0126] Assessment of neurological function ERGs are used to characterize neuronal function. ERG responses to full-field stimuli over a range of intensities are recorded from dark-adapted animals as detailed previously (Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9). Summarizing the activity of rod photoreceptors, a model of phototransduction activation is fitted to the a-wave and the resulting sensitivity (SROD) and saturation amplitude (RROD) parameters are calculated. Post-receptor activity is represented by the b-wave. The stimulus / response function is summarized by the stimulus that produces the saturation amplitude (Vmax) and the half-maximal response (log s); these parameters are derived from a Michaelis-Menten function fit to the b-wave amplitude (Hood Birch, Invest. Ophthalmol. Vis. Sci., (1994) 35: 2948-2961; Lamb, and Pugh, J. Physiol. (Lond). (1992) 449: 719-758; Pugh. and Lamb, Biochim. Biophys. Acta, 1993. 1141: 111-149;Pugh and Lamb, in Handbook of biological physics. Volume 3 (2000), Elsevier Science. p. 183-255; Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9).

[0127] Assessment of vascular characteristics Retinal vascular parameters can be derived using image analysis software and applied to digital fundus photographs (Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9; Martinez-Perez, ME, (2001), Imperial College: London; Martinez-Perez et al., Trans. Biomed. Eng., (2002) 49: 912-917). Integral curvature (IC) is in good agreement with subjective assessments of vascular tortuosity reported by experienced clinicians and can be used to characterize the vascular status of each fundus (Gelman, RM Invest. Ophthalmol. Vis. Sci., (2005) 46(12): 4734-4738). Both arterioles and venules are significantly affected by ROP. However, it has been determined that arterioles are significantly affected, whereas venules are less affected; therefore, arteriolar parameter ICA is used for the analysis described herein (Akula et al., Ophthalmol. Vis. Sci., (2007) 48: 4351-9; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 5447-52; Liu et al., Invest. Ophthalmol. Vis. Sci., (2006) 47: 2639-47; Gelman, R., M. Invest. Ophthalmol. Vis. Sci., (2005) 46(12): 4734-4738). Relationship between retinal sensitivity and vascular system

[0128] Rod photoreceptor sensitivity (SROD) at an early age (20 days) is used to predict retinal vascular outcome as evidenced by ICA. Better sensitivity at an early age is associated with better (less tortuous) vascular outcome (Akula et al., Invest. Ophthalmol. Vis. Sci., (2007) 48: 4351-9). After cessation of exposure to induced oxygen, recovery of postreceptor neural retinal sensitivity (b-wave log s) returns and vascular tortuosity decreases. Regulation of retinal neuronal and vascular development occurs under the coordinated control of several growth factors, e.g., vascular endothelial growth factor (VEGF), semaphorins and their neuropilin receptors (Gariano et al., Gene Expression Patterns, (2006) 6: 187-192). In a rat model of ROP, the expression of these growth factors was confirmed to be altered (Mocko et al., ARVO Absract, (2008)).

[0129] Also described herein is a method of treating wet age-related macular degeneration in a patient, comprising administering to the patient a therapeutically effective amount of a visual cycle modulation (VCM) compound.

[0130] Visual Cycle Modulation As used herein, "visual cycle modulation" (VCM) refers to the biological conversion of photons into electrical signals in the retina (see, e.g., Figures 1A and 1B). The retina contains photoreceptor cells known as "rods" (responsible for night vision) and "cones" (responsible for day vision). Rod cells are much more numerous and more active than cones. Overactivity of rods leads to the accumulation of toxins in the eye, while cones provide the majority of our visual information, including color. VCM essentially "slows down" rod activity, reducing metabolic load and oxygen consumption in the retina. Figure 4B illustrates one means by which VCM affects the visual cycle.

[0131] Described herein are VCM compounds useful for improving the outcome of ROP. The VCM compounds may be administered alone or with one or more additional compounds / treatments, including but not limited to, treatments that can reduce vascular growth in those cases where drug treatments that reduce the energy demand of rod photoreceptors are not suitable, and environmental treatments that enhance the light to which the patient is exposed. According to the physiology of rod photoreceptors, metabolic demand is highest in conditions of low light; therefore, exposure to enhanced light can reduce metabolic demand, thereby alleviating the symptoms of ROP.

[0132] Macular degeneration Macular degeneration refers to the loss of photoreceptors in the part of the central retina called the macula, which is responsible for high-acuity vision. Macular degeneration is associated with abnormal accumulation of extracellular matrix components and debris in the membrane between the retinal pigment epithelium and the vascular choroid. This debris-like material is called drusen. Drusen are visible during fundus examination. Normal eyes have a drusen-free macula, and drusen may also be abundant in the retinal periphery. The presence of soft drusen in the macula without any loss of macular vision is considered an early stage of AMD.

[0133] Age-related macular degeneration Age-related macular degeneration (AMD) refers to diseases that cause abnormalities in the macula of the retina; it is the main cause of vision loss in Europe and the United States. In Japan, the disease is steadily increasing due to the aging population. The macula is located in the center of the retina, an area densely populated with cone cells among the photoreceptor cells. Light rays coming from the outside are refracted by the cornea and the lens, and then focused on the macula, especially the fovea. The ability to read depends on the function of this area. In age-related macular degeneration, the macula, a critical area as mentioned above, degenerates with age, causing vision problems, mainly image distortion (strabismus) and central scotoma.

[0134] Central geographic atrophy is the "dry" form of advanced AMD, which results from atrophy of the lower retina down to the retinal pigment epithelium layer, resulting in loss of vision due to loss of photoreceptors (rods and cones) in the center of the eye. Neovascular or exudative AMD is the "wet" form of advanced AMD, which reduces vision due to abnormal proliferation of blood vessels (choroidal neovascularization) at the choriocapillaris, penetrating Bruch's membrane, and ultimately leaking blood and proteins into the lower macula. If left untreated, bleeding, leakage, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors, resulting in rapid vision loss. The wet form of age-related macular degeneration is a disease with a poor prognosis and rapidly causes severe vision loss. The primary pathology is choroidal neovascularization.

[0135] Age-related macular degeneration (AMD) is one of the leading causes of blindness in developed countries. The approval of the macromolecules LUCENTIS®, AVASTIN®, and MACUGEN® has improved available treatment options for AMD patients. LUCENTIS® is a Fab and AVASTIN® is a monoclonal antibody. Both bind to vascular endothelial growth factor (VEGF) and can be used to treat AMD; however, only a minority of treated patients experience significant improvement in vision.

[0136] choroidal neovascularization Choroidal neovascularization (CNV) refers to the formation of new blood vessels in the choroid layer of the eye. CNV can rapidly result in individuals with defects in Bruch's membrane, the innermost layer of the choroid. Furthermore, it is associated with excessive amounts of vascular endothelial growth factor (VEGF). Similar to wet AMD, CNV is also often associated with the rare genetic disease pseudoxanthoma elasticum, and rarely with the more common optic disc drusen. CNV is also associated with high myopia or malignant myopic degeneration, but choroidal neovascularization primarily results from the presence of cracks in the retina (especially) macular tissue, known as lacquer cracks.

[0137] CNV can cause sudden deterioration of central vision, significant within a few weeks. Other symptoms that may occur include image distortion and color vision disorders. Hemorrhage of new blood vessels can accelerate the onset of symptoms of CNV.

[0138] CNV can be detected by Preferential Hyperacuity Perimeter measurements. Based on fluorescein angiography, CNV can be described as typical or occult. PHP is a specialized peripheral perimetry that applies the principles of both static and automated perimetry to detect defects in the visual field. Rather than measuring the peripheral field, PHP measures subtle differences between central and paracentral fields through the concept of hyperacuity. Hyperacuity is the ability to discern subtle deviations of objects. Hyperacuity, or vernier acuity, has a threshold of 3-6 arc seconds at the fovea. Thus, the threshold for hyperacuity is about 10 times lower than that required for optimal resolution of objects, which is 30-60 arc seconds at the fovea.

[0139] Choroidal neovascularization (CNV) commonly occurs in macular degeneration, as well as other ocular disorders, and is associated with proliferation of choroidal endothelial cells, overproduction of extracellular matrix, and formation of fibrovascular subretinal membranes. Retinal pigment epithelial cell proliferation and production of angiogenic factors are thought to influence choroidal neovascularization.

[0140] The current standard of treatment in retinology today is intravitreal injection of anti-VEGF agents to control neovascularization and reduce the area of ​​fluid below the retinal pigment epithelium. These agents are commonly known as AVASTIN® and LUCENTIS®. And although their efficacy has been suggested to significantly improve visual prognosis from CNV, recurrence rates for these neovascular areas remain high. It should be noted that individuals with CNV are at much higher risk (25%) of developing CNV in the fellow eye according to the American Academy of Ophthalmology and further supported clinical reports.

[0141] In "wet" (also known as "neovascular") age-related macular degeneration, CNV is treated with photodynamic therapy in conjunction with a photosensitizer (e.g., verteporfin). Verteporfin, a benzoporphyrin derivative, is an intravenous lipid-soluble photosensitizer with an absorption peak at 690 nm. The drug was first approved by the Food and Drug Administration (FDA) on April 12, 2000, and subsequently approved for inclusion in the United States Pharmacopeia on July 18, 2000, and meets Medicare's definition of a drug when administered intravenously by a physician in conjunction with ocular photodynamic therapy (see §80.2, "Photodynamic Therapy"). For patients with age-related macular degeneration, verteporfin is only indicated for a diagnosis of neovascular age-related macular degeneration (ICD-9-CM 362.52) with predominantly classic subfoveal choroidal neovascular (CNV) lesions (where the area of ​​typical CNV occupies >50 percent of the total lesion area) as determined by fluorescein angiography (CPT code 92235) at the initial visit. Subsequent follow-up visits require fluorescein angiography before treatment. OPT with verteporfin applies to the above indications and remains exempt from all other indications related to AMD (see §80.2). OPT with verteporfin used in conditions other than AMD is subject to the discretion of the individual physician+. Verteporfin is administered intravenously. It is then activated in the eye by laser light. The drug destroys new blood vessels and also prevents any new blood vessels that may result from thrombus formation.

[0142] Anti-VEGF drugs, such as pegaptanib and ranibizumab, are also used to treat CNV. Anti-VEGF binds to and inactivates VEGF.

[0143] CNV refers to the ectopic proliferation of choroidal blood vessels penetrating Bruch's membrane and the retinal pigment epithelium. In wet age-related macular degeneration, bleeding and leakage of plasma components, including lipids, from the immature vascular plexus are the direct causes of rapid dysfunction of the neural retina. CNV is thought to be induced by inflammatory cells, mainly macrophages, that infiltrate to phagocytose drusen accumulated in the subretinal macular region. Inflammatory cells such as macrophages are also the source of angiogenic factors, such as vascular endothelial growth factor (VEGF), which function to promote angiogenesis at the site of inflammation. This process is called "inflammatory angiogenesis". At the same time, drusen contain advanced glycation end products (AGEs) and amyloid beta, which are substances that stimulate VEGF production; these substances, which migrate to envelop the drusen, stimulate the retinal pigment epithelium, resulting in the secretion of VEGF, which is another possible mechanism of CNV development. Diseases associated with CNV include myopic choroidal neovascularization and idiopathic choroidal neovascularization, as well as age-related macular degeneration. The onset of diseases associated with CNV can sometimes be caused by retinal pigmented streaks, injury, uveitis, etc. It has been suggested that tissue injury and subsequent inflammation, mainly consisting of Bruch's membrane and retinal pigment epithelium in the subretinal macular region, are involved in the mechanism of CNV onset in these diseases and age-related macular degeneration.

[0144] Medical procedures requiring prolonged exposure of the eye Most ocular surgeries, procedures, treatments and examinations require direct and often sustained exposure of the eye to bright light; the compounds described herein are useful in limiting or preventing unwanted damage to the eye due to such exposure.

[0145] Some medical procedures are aimed at correcting structural defects in the eye.

[0146] Refractive eye surgery includes various methods for surgical restructuring of the cornea or cataract (e.g., radial keratectomy uses spoke-shaped incisions with a diamond knife). In some cases, an excimer laser is used to reshape the curvature of the cornea. In some cases, refractive eye surgery can reduce or correct common vision disorders such as myopia, hyperopia, and astigmatism, as well as degenerative disorders such as keratoconus. Other types of refractive eye surgery include keratomileusis (removal of the corneal papilla, flash freezing, milling and grinding, followed by restoration of its original curvature), automated lamellar keratoplasty (ALK), laser-assisted myopia surgery (LASIK), intra-LASIK, laser-assisted subepithelial keratomileusis (LASEK aka Epi-LASIK), laser photorefractive keratectomy, laser thermal keratoplasty, conduction keratoplasty, limbal relaxing incisions, astigmatic keratotomy, radial keratotomy, mini asymmetric radial keratotomy, hexagonal keratotomy, lamellar keratoplasty, intracorneal ring or intracorneal ring implants (Intacs), contact lens implants, presbyopia inversion, anterior ciliary sclerotomy, laser inversion of presbyopia, scleral expansion bands, etc. bands, and Camel Inlay.

[0147] Corneal surgery includes, but is not limited to, corneal transplant surgery, penetrating keratoplasty, keratoprosthesis, therapeutic lamellar keratotomy, pterygium resection, keratochromocytoma, and odontogenic keratoprosthesis (OOKP). In some cases, corneal surgery does not require a laser. In other cases, corneal surgery uses a laser (e.g., therapeutic lamellar keratotomy, which removes superficial corneal opacities and surface irregularities). In some cases, patients are provided with sunglasses to protect their eyes from bright light after these procedures.

[0148] Some procedures aim to remove obstructing materials or fluids from the eye.

[0149] Cataract surgery involves the surgical removal of the lens and its replacement with a plastic intraocular lens. Light is typically used to assist the surgeon.

[0150] There are various types of glaucoma surgeries that promote excess aqueous humor outflow from the eye and reduce intraocular pressure. In some cases, these medical procedures use lasers (e.g., laser trabeculoplasty applies laser light to burn areas of the trabecular meshwork located near the base of the iris, increasing fluid outflow; laser peripheral iridotomy applies laser light to selectively burn holes near the base of the iris periphery; etc.). Schlemm's canaloplasty is an advanced non-penetrating procedure that utilizes microcatheter technology in a simple and minimally invasive procedure and is designed to promote drainage through the eye's natural drainage system. Other medical procedures used to treat glaucoma include lasers, non-penetrating surgery, protective filtration surgery, and seton valve implants.

[0151] Vitreoretinal surgery includes vitrectomy (eg, anterior vitrectomy and pars plana vitrectomy). In some cases, vitreoretinal surgery is used to prevent or treat vitreous loss during cataract or corneal surgery, remove ectopic vitreous tissue in conditions such as aphakic pupil-occlusive glaucoma, remove vitreous opacities and membranes through incisions, retinal detachment repair (using stinging, scleral buckles, or laser photocoagulation, pneumatic retinopexy, retinal cryopexy, or retinal coagulation), macular hole repair, partial lamellar sclerouvectomy, partial lamellar sclerocyclochoroidectomy, partial lamellar sclerochoroidectomy, posterior sclerotomy, radial optic nerve tomography, and macular translocation. Panretinal photocoagulation (PRP), a type of photocoagulation laser treatment often used in the treatment of diabetic retinopathy, aims to treat vitreous hemorrhage, lesions, retinal tears, subarachnoid hemorrhage, or intraocular bleeding due to blood clots. In some cases, laser photocoagulation shrinks unhealthy blood vessels or seals retinal tears once the blood has been removed.

[0152] Some medical procedures address structures or features that maintain the function or appearance of the eye. Eye muscle surgery typically corrects strabismus and includes: relaxation and weakening procedures (e.g., recession, myectomy, myotomy, tenotomy, tenotomy, tightening, etc.), strengthening procedures (e.g., resection, tucking, moving eye muscles from their natural attachment on the eyeball to a more anterior position, etc.); transposition and reduction, and adjustable suture procedures (e.g., reattachment of extraocular muscles with stitches that can be shortened or lengthened to achieve better eye position within one day after surgery).

[0153] Oculoplastic surgery, or oculoplastics, is a sub-specialty of ophthalmology that deals with the reconstruction of the eye and associated structures, including eyelid surgery, treatment of blocked lacrimal ducts, treatment of orbital fractures, removal of intraocular and periocular tumors, and facial rejuvenation procedures, such as laser skin treatments, eyelid lift, brow lift, cheek wrinkle removal, Botox injections, Ultrapeel microdermabrasion, and liposuction. Some eye procedures improve the lacrimal apparatus, including, for example, canaliculostomy, canaliculosastomy, canaliculotomy, lacrimal gland resection, dacryocystectomy, and dacryocystostomy.

[0154] Visual Cycle Modulating Compounds As used in this specification and the appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0155] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, a reference to "the cell" includes a reference to one or more cells (or to a number of cells), and equivalents thereof known to those of skill in the art, and so forth. Further, for example, a reference to "the method" includes one or more methods and / or steps of the type described herein and / or that will become apparent to those of skill in the art upon reading this disclosure, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments herein are intended to be included. The term "about," when referring to a number or numerical range, means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") does not exclude that in other specific embodiments, the embodiments, e.g., any composition of matter, composition of matter, method or process described herein, "consist of" or "consist essentially of" the described features.

[0156] "Amino" refers to the group -NH2.

[0157] "Cyano" refers to the radical -CN.

[0158] "Nitro" refers to the -NO2 group.

[0159] "Oxa" refers to the group --O--.

[0160] "Oxo" means the group ═O.

[0161] "Thioxo" refers to the group ═S.

[0162] "Imino" refers to the =NH group.

[0163] "Hydrazino" means the =N-NH2 group.

[0164] "Alkyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, alkyl comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl comprises 5 to 15 carbon atoms (e.g., C5-C 15 In another embodiment, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). An alkyl group is attached to the remainder of the molecule by a single bond, e.g., methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise in the specification, an alkyl group may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a(wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2) and -S(O) t N(R a ) 2, where t is 1 or 2, where R a Each is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0165] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2) and -S(O) t N(R a ) 2, where t is 1 or 2, where R aEach is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0166] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl has from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, an alkynyl group may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2) and -S(O) t N(R a ) 2, where t is 1 or 2, where R a Each is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0167] "Alkylene" or "alkylene chain" means a straight or branched divalent hydrocarbon chain, consisting only of carbon and hydrogen, containing no unsaturation, having from 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., that attaches the rest of the molecule to a radical group. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons in the chain. Unless stated otherwise in the specification, an alkylene chain can be optionally substituted with one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2) and -S(O) t N(R a ) 2, where t is 1 or 2, where R a Each is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0168] "Alkenylene" or "alkenylene chain" means a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one double bond, having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons in the chain. Unless stated otherwise in the specification, an alkenylene chain can be optionally substituted with one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2) and -S(O) t N(R a ) 2, where t is 1 or 2, where R a Each is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each of the above substituents is unsubstituted unless otherwise specified.

[0169] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, where at least one of the rings of the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) pi-electron system according to the Huckel theory. Aryl groups include, but are not limited to, groups such as phenyl, fluorenyl, and naphthyl. As used herein, unless stated otherwise, the term “aryl” or the prefix “ar-” (e.g., “aralkyl”) includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a(wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a aryl groups, optionally substituted with one or more substituents independently selected from R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, where each of the above substituents are unsubstituted unless otherwise specified.

[0170] "Aralkyl" is a group of the formula -R c -aryl group, where R c is an alkylene chain as defined above, e.g., benzyl, diphenylmethyl, etc. The alkylene chain portion of the aralkyl group may be optionally substituted as described above for an alkylene chain. The aryl portion of the aralkyl group may be optionally substituted as described above for an aryl group.

[0171] "Aralkenyl" is a group of the formula -R d -aryl group, where R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group may be optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl group may be optionally substituted as defined above for an alkenylene group.

[0172] "Aralkynyl" refers to a group of the formula -Re -aryl group, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group may be optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl group may be optionally substituted as defined above for an alkynylene chain.

[0173] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which may contain fused or bridged ring systems, having from 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains from 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains from 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl may be saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also referred to as "cycloalkyls". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise in the specification, the term "carbocyclyl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -Rb -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2, a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, where each of the above substituents are unsubstituted unless otherwise specified.

[0174] A "carbocyclylalkyl" is a group of the formula -R c -carbocyclyl group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group may be optionally substituted as defined above.

[0175] "Halo" or "halogen" means a bromo, chloro, fluoro or iodo substituent.

[0176] "Fluoroalkyl" means an alkyl group, as defined above, that is substituted with one or more fluoro groups, as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group may be optionally substituted as defined above for an alkyl group.

[0177] "Heterocyclyl" means a stable 3- to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated in the specification, a heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms of a heterocyclyl group may be optionally oxidized. If present, one or more nitrogen atoms may be optionally quaternized. A heterocyclyl group is partially or fully saturated. A heterocyclyl may be attached to the remainder of the molecule through any atom of the ring(s). Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, the term "heterocyclyl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -SR a , -Rb -OC(O)-R a , -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a ) 2, where t is 1 or 2, wherein R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise specified.

[0178] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl group as defined above containing at least one nitrogen, where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a nitrogen atom in the heterocyclyl group. The N-heterocyclyl group may be optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0179] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl group as defined above containing at least one heteroatom, where the point of attachment of said heterocyclyl group to the rest of the molecule is through a carbon atom within the heterocyclyl group. The C-heterocyclyl group may be optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0180] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclyl, where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl group may be optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl group may be optionally substituted as defined above for a heterocyclyl group.

[0181] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, where at least one of the rings of the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) pi-electron system according to the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl group may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heteroaryl is bonded to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6 ]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (e.g., thienyl). Unless otherwise stated in this specification, the term "heteroaryl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -SR a , -R b -OC(O)-R a , -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a) 2, where t is 1 or 2, wherein R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise specified.

[0182] "N-heteroaryl" means a heteroaryl group as defined above containing at least one nitrogen, where the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group may be optionally substituted as described above for heteroaryl groups.

[0183] "C-heteroaryl" means a heteroaryl group as defined above, where the point of attachment of said heteroaryl group to the rest of the molecule is through a carbon atom within the heteroaryl group. C-heteroaryl groups may be optionally substituted as described above for heteroaryl groups.

[0184] "Heteroarylalkyl" refers to R c is an alkylene chain as defined above; c -heteroaryl. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group may be optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl group may be optionally substituted as defined above for a heteroaryl group.

[0185] The compounds, or their pharma- ceutically acceptable salts, may have one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that can be de?ned in terms of absolute stereochemistry as (R)- or (S)- of amino acids, or as (D)- or (L)-. Where the compounds described herein have ole?nic double bonds or other centers of geometric asymmetry, and unless otherwise speci?ed, it is intended that the compounds include both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as Well as their racemic and optically pure forms, and all tautomers are also intended to be included.

[0186] "Stereoisomer" means a compound consisting of the same atoms linked by the same bonds, but having different, non-interchangeable three-dimensional structures. Thus, various stereoisomers and mixtures thereof are contemplated, including "enantiomers," which means two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0187] The compounds presented herein may exist as tautomers. "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule accompanied by isomerization of adjacent double bonds. When bonding positions where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include: [ka] Examples include:

[0188] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description is meant to include the occurrence or non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and the description is meant to include both substituted and unsubstituted aryl groups.

[0189] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the substituted heterocyclic amine derivative compounds described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0190] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997), which is incorporated herein by reference in its entirety.) Acid addition salts of basic compounds can be prepared by reacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques well known to those skilled in the art.

[0191] By "pharmaceutical acceptable base addition salt" is meant a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0192] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, thereby resulting in improvement in the patient, even though the patient still suffers from the underlying disease. With regard to prophylactic benefit, the composition can be administered to a patient at risk of developing a particular disease or to a patient who complains of one or more physiological symptoms of a disease, even if the patient has not been diagnosed with the disease.

[0193] "Prodrug" is meant to indicate a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharma- ceutical acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted in vivo, for example by hydrolysis, into an active compound. Prodrug compounds often confer advantages of solubility, tissue compatibility, or sustained release to mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (Elsevier, Amsterdam)).

[0194] Prodrugs are discussed in Higuchi, T., et al., "Pro drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0195] The term "prodrug" is also meant to include any covalently bonded carrier, which releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound.

[0196] Compositions and Methods of Administration In some embodiments, the compounds described herein are formulated as pharma- ceutically acceptable compositions when combined with an acceptable carrier or excipient.

[0197] Thus, in some embodiments, the compositions contain, in addition to the active ingredient, acceptable excipients, carriers, buffers, stabilizers, or other materials known in the art for use in compositions administered to a patient. Such materials are non-toxic and do not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other substance will depend on the route of administration.

[0198] Acceptable carriers and their formulation generally are described in, for example, Remington's Pharmaceutical Sciences (18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA 1990).

[0199] Compositions are formulated to be suitable with a particular route of administration in mind, and thus may contain carriers, diluents or excipients suitable for administration by various routes.

[0200] A "therapeutically effective amount" of a composition to be administered is the minimum amount necessary to prevent, ameliorate or treat a disease or disorder. The composition is optionally formulated with one or more drugs currently used to prevent or treat the disorder. The effective amount of such other drugs depends on the amount of compound present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosage and route of administration as used herein above, or about 1-99% of the dosage used above. In general, mitigation or treatment of a disease or disorder includes alleviating one or more symptoms or medical problems associated with the disease or disorder.

[0201] The compounds described herein may be administered in any manner suitable to effectively achieve the desired ocular therapeutic effect, including, but not limited to, topical, intraocular (including intravitreal), transdermal, oral, intravenous, subconjunctival, subretinal, or intraperitoneal routes of administration.

[0202] Administration techniques that can be used in the compounds and methods are known in the art and described herein, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the compounds and compositions described herein are administered orally.

[0203] The liquid dosage form for oral administration can be an aqueous suspension, such as a pharma- ceutically acceptable aqueous oral dispersion, emulsion, solution, elixir, gel, and syrup.See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to the compound, the liquid dosage form may optionally contain a pharma- ceutically acceptable carrier or additive suitable for oral administration, and may optionally contain one or more additives such as: (a) disintegrants; (b) dispersants; (c) wetting agents; (d) preservatives; (e) thickeners; (f) sweeteners, and / or (g) flavoring agents.In some embodiments, the aqueous dispersion further comprises a crystal formation inhibitor.

[0204] In one embodiment, an emulsifier and / or suspending agent may be added to the composition along with a diluent, such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0205] Water can be added (e.g., 5%) as a means of simulating long-term storage to determine properties such as the shelf life or stability of a formulation over time. Anhydrous compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Lactose-containing compositions and dosage forms can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous compositions can be prepared and stored such that their anhydrous nature is maintained. Anhydrous compositions can thus be included in suitable formulary kits by packaging them using materials known to prevent exposure to water.

[0206] In further or alternative embodiments, the composition may be in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension or emulsion.

[0207] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.

[0208] In such solid dosage forms, the compositions described herein contain at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, or the like. The composition may be mixed with, for example, sodium, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may further comprise a buffering agent.

[0209] Solid compositions of a similar type can also be used as fillers for soft and hard filled gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycols. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned additives. In preparing pharmaceutical formulations as disclosed herein in unit dosage form for oral administration, the selected compound can be mixed with solid pulverized ingredients, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients, as well as with disintegrants and lubricants, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. The mixture is then processed into granules or compressed into tablets.

[0210] The composition may be in a unit dosage form suitable for single administration of a precise dose. In further or additional embodiments, the amount of the compound ranges from about 0.001 to about 1000 mg / kg body weight / day. In further or additional embodiments, the amount of the compound ranges from about 0.5 to about 50 mg / kg body weight / day. In further or additional embodiments, the amount of the compound is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound is from about 0.002 to about 6 g / day. In further or additional embodiments, the amount of the compound is from about 0.005 to about 5 g / day. In further or additional embodiments, the amount of the compound is from about 0.01 to about 5 g / day. In further or additional embodiments, the amount of the compound is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of the compound is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of the compound is from about 0.1 to about 1 g / day. In some embodiments, dosage levels below the lower limit of the aforementioned ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the aforementioned range may be required.

[0211] In one embodiment, the daily dose of (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol is from about 4 mg to about 100 mg. In another embodiment, the daily dose of (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol is about 2 mg; about 5 mg; about 7 mg; about 10 mg; about 15 mg; about 20 mg; about 40 mg; about 60 mg; about 75 mg; or about 100 mg.

[0212] In some embodiments, a composition for oral delivery contains at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% of a compound described herein. In other embodiments, a composition for oral delivery contains at least about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, or 100% of a compound described herein. In some embodiments, a composition contains about 1-100%, about 10-100%, about 20-100%, about 50-100%, about 80-100%, about 90-100%, about 95-100%, or about 99-100% of a compound described herein. In some embodiments, the composition contains about 1-90%, about 10-90%, about 20-90%, about 50-90%, or about 80-90% of a compound described herein. In some embodiments, the composition contains about 1-75%, about 10-75%, about 20-75%, or about 50-75% of a compound described herein. In some embodiments, the composition contains about 1-50%, about 10-50%, about 20-50%, about 30-50%, or about 40-50% of a compound described herein. In some embodiments, the composition contains about 1-40%, about 10-40%, about 20-40%, or about 30-40% of a compound described herein. In some embodiments, the composition contains about 1-30%, about 10-30%, or about 20-30% of a compound described herein. In some embodiments, the composition contains about 1-20%, or about 10-20% of a compound described herein. In some embodiments, the compositions contain about 1-10% of a compound described herein.

[0213] treatment method Provided herein is a method of treating diabetic retinopathy in a patient (alleviating one or more symptoms, or the cessation of one or more symptoms) by administering to the patient a therapeutically effective amount of a composition provided herein. Treatment can improve the patient's condition, and can be assessed by determining one or more of the following factors: whether a reduction in macular edema or an improvement in visual acuity has occurred. The compounds described herein can also be used as medicaments for the treatment of diabetic retinopathy.

[0214] A "patient" is a mammal that exhibits one or more clinical symptoms and / or symptoms of a disease or disorder described herein. Non-limiting examples of patients include, but are not limited to, humans or non-human animals, such as primates, rodents, cows, horses, pigs, sheep, etc. In certain circumstances, a patient may be asymptomatic or may still have clinical symptoms of a disease or disorder. In one embodiment, the patient being treated is a human.

[0215] The compositions provided herein can be administered once or multiple times, depending on the patient's health, the progression of the disease or condition, and the effectiveness of the treatment. Adjustments to therapy and treatment can be made throughout the treatment plan.

[0216] Signs and symptoms of diabetic retinopathy include, but are not limited to, one or more of the following: degeneration of blood vessels; swelling of the retina (macular edema); pale deposits on the retina; damage to nerve tissue; visual appearance of vascular leakage; loss of central or peripheral vision; temporary or permanent loss of vision; spots, blurring, cloudiness or diplopia; eye pain; floaters; impaired color vision; decreased visual acuity; dark areas or areas of difficulty in the central field; enlarged veins and intraretinal microvascular abnormalities; neuropathy; fluctuating and progressive worsening of vision; macular edema; macular ischemia; tractional retinal detachment; endothelial cell proliferation; photopsia; rubeosis or nvi; microaneurysms; hard exudates; hemorrhages; and cotton wool spots are symptoms associated with diabetic retinopathy.

[0217] In one embodiment, treating DR with the compounds described herein inhibits abnormal angiogenesis, slows vascular leakage, reduces retinal swelling, prevents retinal detachment, prevents or delays blindness, and / or reduces vision loss.

[0218] Compounds administered in such methods may be administered by any suitable means, such as those described herein and known in the art.

[0219] For the prevention or treatment of disease, the appropriate dosage of the compound will depend, in part, on the patient being treated, the severity and course of the disease, whether the compound is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's medical history and response to the compound, and the discretion of the attending physician. The compound is suitably administered to the patient at one time or over a series of treatments.

[0220] The composition can be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The amount administered depends on the subject being treated and the ability of the patient's immune system to utilize the active ingredient. The exact amount of the active ingredient required to be administered depends on the judgment of the practitioner and is specific to each individual. In addition, the appropriate regime for initial administration and booster injections can also be modified. Depending on the type and severity of the disease, for example, about 0.1 μg / kg to about 150 mg / kg of the compound is the initial candidate dose administered to the patient, whether by single or multiple divided administrations or by continuous infusion. Other initial doses include, but are not limited to, about 0.25 μg / kg, about 0.5 μg / kg, about 1 μg / kg, about 10 μg / kg, about 50 μg / kg, about 100 μg / kg, about 250 μg / kg, about 500 μg / kg, about 750 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg or more. Thereafter, typical daily doses can range from about 0.1 μg / kg to about 150 mg / kg or more, depending on the factors mentioned above. For continuous administration over several days or more, treatment is continued until a desired suppression of disease symptoms occurs, depending on the condition. However, other dosage regimens may be useful. Dosage can be administered once a day, daily, weekly, monthly, or bimonthly. Additionally, the compound dose(s) can be administered twice weekly, weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 12 weeks, or any combination of the aforementioned weeks. Dosage cycles can also be contemplated, for example, administering the compound once or twice a week for 4 weeks, followed by 2 weeks without treatment. Additional dosing cycles include, for example, different combinations of dosing, and even weekly cycles as described herein are contemplated. One or more symptoms can be evaluated during treatment, and dosing adjusted accordingly. Dosing can be administered orally and / or intravitreally.

[0221] The composition may be administered alone or in combination with a second treatment, either simultaneously or sequentially, depending on the condition being treated. When more than one composition, or composition and treatment, are administered, the compositions or compositions / treatments may be administered in combination (sequentially or simultaneously). The composition may be administered in a single dose or multiple doses.

[0222] The term "unit dose" as used in reference to compositions means physically discrete units suitable for single administration to human beings, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with the required diluent, i.e., carrier, or vehicle.

[0223] Depending on the type and severity of the disease, for example, about 0.1 μg / kg to about 150 mg / kg of the compound is an initial candidate dose administered to a patient, whether by single or multiple divided doses or by continuous infusion. Other initial doses include, but are not limited to, about 0.25 μg / kg, about 0.5 μg / kg, about 1 μg / kg, about 10 μg / kg, about 50 μg / kg, about 100 μg / kg, about 250 μg / kg, about 500 μg / kg, about 750 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg or more. Thereafter, a typical daily dosage can range from about 0.1 μg / kg to about 150 mg / kg or more, depending on the factors mentioned above. For continuous administration over several days or longer, treatment is continued until a desired suppression of disease symptoms occurs, depending on the condition. However, other dosage regimens may be useful.

[0224] In one embodiment, the treatment of a patient suffering from age-related macular degeneration, choroidal neovascularization and / or diabetic retinopathy as described herein includes improvement of at least one of the symptoms as described herein. Improvement includes, for example, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% improvement in one or more signs or symptoms as described herein. The composition can be administered to the patient in a therapeutically effective amount effective to obtain some desired therapeutic effect with a suitable benefit / risk ratio applicable to any medical treatment. When the composition of the present invention is administered to a human patient, the composition can be formulated by methods known to those skilled in the art.

[0225] As used herein, the term "treatment" refers to both therapeutic and preventative measures. Those in need of treatment include those already suffering from the disorder as well as those who wish to prevent the deterioration of the disorder. In one embodiment, treatment of a patient suffering from diabetic retinopathy as described herein means that one or more signs or symptoms do not worsen or progress. In another embodiment, treatment of a patient suffering from age-related macular degeneration and / or choroidal neovascularization as described herein means that one or more signs or symptoms do not worsen or progress. As used herein, "prevention" refers to the prevention of one or more signs or symptoms of diabetic retinopathy, age-related macular degeneration and / or choroidal neovascularization, prevention of onset of symptoms, prevention of progression. As used herein, "inhibition", "treatment" and "treating" are used to refer to, for example, stasis of symptoms, prolongation of survival, partial or full improvement of symptoms.

[0226] "Administering" is defined herein as a means of providing a composition to a patient in a manner that results in the composition being present in the patient's body. Such administration may be by any route, including, but not limited to, the modes of administration described herein or those routinely known in the art. "Concurrent administration" means administration within a relatively short time period; such time period may be less than 2 weeks, less than 7 days, less than 1 day, and may be administered simultaneously.

[0227] The actual dosage level of the active ingredient in the composition can be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic effect for a particular patient, composition, and mode of administration without toxicity to the patient. The selected dosage level will depend on a variety of factors, such as the activity of the particular compound used, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular composition used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0228] In one embodiment, the compound can be administered in a single dose, once daily. In another embodiment, the compound can be administered in multiple doses, two or more times daily. In another embodiment, the compound can be administered twice daily. In another embodiment, the compound can be administered three times daily. In another embodiment, the compound can be administered four times daily. In another embodiment, the compound can be administered five or more times daily.

[0229] A response is achieved when a patient experiences a partial or total alleviation or reduction, including but not limited to, prolonged survival, of signs or symptoms of the disease. Expected progression-free survival depends on prognostic factors, including the number of relapses, stage of the disease, and other factors, and can be measured in months to years. Prolonged survival includes, but is not limited to, at least 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 3 years, or longer. Overall survival can also be measured in months to years. The patient's symptoms can remain static or can be alleviated.

[0230] A physician or veterinarian having ordinary skill in the art will determine the effective amount (ED) of the composition required. 50 ) can be readily determined and prescribed. For example, a physician or veterinarian can begin dosing the compounds used in the composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. Alternatively, the dosage can be maintained constant.

[0231] The toxicity and therapeutic efficacy of such components are determined, for example, by LD 50 (lethal dose for 50% of the population) and ED 50 The determination of the therapeutically effective dose (the amount therapeutically effective in 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Compounds that exhibit toxic side effects may be used, but care should be taken to design a delivery system that targets delivery of such compounds to the site of affected tissue in order to minimize potential damage to healthy cells, thereby reducing side effects.

[0232] Also provided herein are methods of treating retinopathy of prematurity (ROP) in a patient in need thereof by administering a composition containing a compound described herein.

[0233] Provided herein are methods for treating or preventing retinopathy of prematurity, comprising administering to a patient in need thereof a composition comprising a visual cycle modulator (VCM) compound as described herein.

[0234] In one embodiment, the compounds alter the visual cycle.The patient treated in this manner is a premature infant.

[0235] In another embodiment, the patient is further treated with supplemental oxygen.

[0236] In another embodiment, the treatment is administered locally to the eye or systemically.

[0237] Provided herein is the use of the visual cycle modulators described herein in the formulation of a medicament for treating retinopathy of prematurity.The treatments described herein can be administered and monitored by a physician.The specific measurement of administration route, dosage and effect can be selected by the administering physician and can depend on factors such as the severity of the patient's disease, age, weight and sex, as well as other factors, such as other medical problems of the patient.

[0238] The efficacy of any given composition can also be determined using an experimental animal model, such as the ROP rat model described herein. When using an experimental animal model, the therapeutic efficacy can be assessed when a reduction in a marker or symptom of ROP is observed.

[0239] The amount and frequency of administration will also depend in part on the composition itself, its stability and specific activity, and the route of administration. Large amounts of a composition must generally be administered systemically as compared to compositions that are administered locally / topically.

[0240] The eye provides a tissue or structure that is highly suitable for the local administration of many drugs. Intraocular injection and oral administration may also be effective. Dosage depends on the route of administration and may vary, for example, from about 0.1 mg / kg body weight to about 10 mg / kg body weight by systemic administration, and from 0.01 mg to 10 mg by topical or intraocular injection routes. Other dosages are also contemplated herein.

[0241] A "therapeutically effective amount" of a composition to be administered is adapted according to such considerations and is the minimum amount necessary to prevent, ameliorate, or treat a disease or disorder. The composition need not be formulated with one or more agents currently used to prevent or treat the disease in question, but may be formulated in some cases. The effective amount of such other agents will depend on the amount of compound present in the formulation, the type of disorder or treatment, and other factors discussed above. These will generally be used in the same dosages and routes of administration used above, or from 1 to 99% of the dosages previously used. In general, mitigation or treatment of a disease or disorder includes the reduction of one or more symptoms or medical problems associated with the disease or disorder.

[0242] Generally, a compound is determined to be "therapeutically effective" in the methods described herein if (a) a measurable symptom or symptoms of, for example, vascular abnormality are reduced, for example by at least 10%, as compared to measurements before treatment began, (b) disease progression is halted (e.g., the patient does not deteriorate or pathological growth of the vasculature is halted), or (c) symptoms are alleviated or improved, for example, as measured by a reduction in blood vessel number or vascular tortuosity. The efficacy of treatment can be determined by a physician, typically as described herein and as known in the art.

[0243] The compositions described herein can also be administered in a prophylactically or therapeutically effective amount. By prophylactically or therapeutically effective amount is meant the amount necessary to obtain the desired effect, at least in part, or to delay the onset, inhibit the progression, or completely stop the onset or progression of the particular disease or disorder being treated. Of course, such amounts will depend on the particular condition being treated, the severity of the condition, and the individual patient parameters, such as age, physical condition, size, weight, and concurrent treatments. These factors are well known to those skilled in the art and can be addressed with no more than routine experimentation. In general, it is preferred to use the highest dosage, i.e., the highest safe dosage according to sound medical judgment. However, those skilled in the art will understand that lower or tolerated dosages can be administered for either medical, psychological, or other practical reasons.

[0244] As used herein, "improving rod-mediated retinal function" means enhancing rod-mediated retinal function by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more.

[0245] "Rod-mediated retinal function" refers to the function of rod cells in a functioning retina, including, for example, clinical endpoints such as peripheral vision, low-level light vision, degree of scotopic / "night vision", and sensitivity to peripheral motion. Rod-mediated retinal function can be assessed in vivo, for example, by electroretinography measurement of rod activation of phototransduction or deactivation of phototransduction; recovery of dark current after photobleaching; measurement of ERGa waves or b-waves; speed of recovery to phototransduction; or rod-mediated response amplitude. Methods for measuring rod-mediated retinal function are known in the art and / or described in detail herein.

[0246] The effectiveness of the treatment can be monitored by the administering clinician. When the disease or disorder is retinopathy of prematurity, the International Classification of Retinopathy of Prematurity (ICROP) can be applied. ICROP uses a series of parameters to classify the disease. These parameters include the placement of the disease into zones (zones 1, 2 and 3), the circumferential extent of the disease based on clock times 1-12, the severity of the disease (stages 1-5), and the presence or absence of "plus disease".

[0247] The zones are centered on the optic nerve. Zone 1 is the posterior zone of the retina, defined as a circle with a radius that doubles the distance extending from the optic nerve to the macula. Zone 2 is an annular portion whose inner edge is defined by Zone 1 and whose outer edge is defined by a radius defined as the distance from the optic nerve to the nasal ora serrata. Zone 3 is the remaining temporal crescent portion of the retina.

[0248] The circumferential extent of the disease is described in segments, as if the upper part of the eye were 12 o'clock on a clock face. For example, stage 1 disease may be reported to be present between 4 o'clock and 7 o'clock, 3 hours apart.

[0249] The stages describe the ophthalmoscopic findings at the junction between the vascular and avascular retina: Stage 1 is a faint border; Stage 2 is a high ridge; Stage 3 is extraretinal fibrovascular tissue; Stage 4 is a subtotal retinal detachment; Stage 5 is a complete retinal detachment.

[0250] Additionally, at any stage, "plus disease" may be present, describing the level of significant vascular dilation and tortuosity observed in the posterior retinal vessels, reflecting increased blood flow throughout the retina.

[0251] Any improvement in ICROP relative to the pretreatment classification is considered to be an effective treatment. Similarly, if prevention of disease is the goal, treatment is considered effective if one or more signs or symptoms (singular or plural) of ROP in the treated individual are less severe than the expected course of the disease in a similar individual not receiving such treatment. The disease is well known and often characterized to such an extent that a skilled physician can predict the extent of disease that may occur in the absence of treatment, for example, based on early patient findings. Failure to progress or experience a worsening of one or more symptoms of ROP, or, for that matter, any other retinal disease or disorder involving abnormal angiogenesis, can be considered effective prevention of disease in an individual who would otherwise be expected to progress or experience a worsening of such disease. Similarly, any improvement to the pathology expected in the absence of treatment can be considered effective treatment.

[0252] As an alternative to the ICROP scale, other clinically accepted markers for retinal disease known to those skilled in the art can also be measured to monitor or determine the effectiveness of the treatment or prevention of a retinal disease or disorder described herein. Generally, a difference of at least 10% is considered significant for markers of retinal disease.

[0253] Provided herein are methods of reducing or inhibiting vascularization (e.g., angiogenesis) in a patient's eye. Also provided herein are methods of treating an angiogenesis-associated ocular disease or disorder in a patient's eye, wherein the angiogenesis-associated ocular disease or disorder is retinal neovascularization. Another embodiment provides a method of treating angiogenesis-associated ocular disease or disorder in a patient's eye, wherein the angiogenesis-associated ocular disease or disorder is choroidal neovascularization. Another embodiment provides a method of treating an angiogenesis-associated ocular disease or disorder in a patient's eye, wherein the angiogenesis-associated ocular disease or disorder is selected from sickle cell retinopathy, Eales' disease, ocular ischemic syndrome, carotid-cavernous sinus fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteriolar disease, radiation retinopathy, retinal vein occlusion, retinal artery occlusion, retinal embolism, birdshot retina-choroidopathy, retinal vasculitis, sarcoidosis, toxoplasmosis, uveitis, choroidal melanoma, chronic retinal detachment, incontinentia pigmenti, and retinitis pigmentosa. Another embodiment provides a method of treating an angiogenesis-associated ocular disease or disorder in a patient's eye, wherein the angiogenesis-associated ocular disease or disorder is wet age-related macular degeneration. Another embodiment provides a method of treating angiogenesis-associated ocular disease or disorder in a patient's eye, wherein the angiogenesis-associated ocular disease or disorder is neovascular age-related macular degeneration.

[0254] Provided herein is a method for treating neovascular age-related macular degeneration (e.g., wet age-related macular degeneration (AMD)) or choroidal neovascularization (CNV) in a patient by administering to the patient a therapeutically effective amount of a composition provided herein. The compounds described herein can also be used in medicaments for the treatment of macular degeneration (e.g., age-related macular degeneration (AMD)) or choroidal neovascularization (CNV). As provided herein, all references to age-related macular degeneration refer to the neovascular or wet stage of the disease.

[0255] Provided herein are methods of treating age-related macular degeneration (AMD) in a patient by administering to the patient a therapeutically effective amount of a composition provided herein. Treatment can improve a patient's condition and can be assessed by determining whether one or more of the following factors have occurred: drusen; pigmentary degeneration; exudative changes (e.g., intraocular hemorrhage, hard exudates, subretinal / sub-RPE / intraretinal fluid); atrophy (early atrophy and geographic atrophy); significant loss of visual acuity (2 or more levels; ex: 20 / 20 to 20 / 80); changes in peripheral hypersensitive fields (for wet AMD); visual impairment (people with non-exudative macular degeneration may be asymptomatic or may notice a gradual loss of central vision, whereas people with exudative macular degeneration often notice a rapid onset of vision loss); central scotoma (shadow or area of ​​missing vision); astigmatism (i.e., metamorphopsia; a grid of straight lines may appear wavy and parts of the grid may appear blank. Patients often first notice this when looking through mini-blinds in their home); impairment with color discrimination (especially dark to dark and light to light); slow recovery of visual function after exposure to bright light; and loss of contrast sensitivity. The present specification describes a method for treating or preventing AMD by administering the compounds described herein.The compounds described herein can also be used in AMD treatment medicine.In one embodiment, one or more signs or symptoms of AMD are improved after administering one of the compounds described herein to a patient.Improvement also includes the cessation of one or more symptoms so that they do not worsen.

[0256] The term "treatment" of a disease associated with CNV means that the symptoms caused by the disease are suppressed or improved. The term "treatment" of a disease associated with CNV also means suppressing the progression of CNV and the dysfunction of the neural retina caused by bleeding or leakage of plasma components from abnormal newly formed blood vessels.

[0257] As used herein, "suppressing CNV" means suppressing retinal inflammation (suppressing the proliferation of retinal inflammatory cells) and suppressing the production of angiogenic factors by inflammatory cells in addition to suppressing angiogenesis. Retinal inflammatory responses can be induced by injury or by the accumulation of metabolic degradation products such as drusen.

[0258] CNV can be confirmed to be suppressed by detecting the size (volume) of angiogenesis using fluorescein angiography or the like.If the volume of angiogenesis is reduced after administration of the drug of the present disclosure, CNV is considered to be suppressed.The method of detecting CNV is, but not limited to, the method described above, and CNV can be detected by known methods, and also by the method described in the examples of this specification.

[0259] As the disease associated with CNV progresses, vision is impaired by image distortion, central scotoma, etc. In the case of such vision impairment, if the vision is improved by administering the compounds described herein, the compounds are considered to be useful for patients suffering from such diseases associated with CNV. Provided herein is a method for treating choroidal neovascularization. The treatment can improve the condition of the patient, which can be evaluated by determining whether the visual acuity has increased. Described herein is a method for treating or preventing choroidal neovascularization by administering the compounds described herein.

[0260] Choroidal neovascularization (CNV) commonly results in macular degeneration in addition to other ocular disorders and is associated with choroidal endothelial cell proliferation, overproduction of extracellular matrix, and formation of a fibrovascular subretinal membrane. Retinal pigment epithelial cell proliferation and production of angiogenic factors are thought to play a role in choroidal neovascularization, choroidal neovascularization (CNV), the development of abnormal blood vessels beneath the retinal pigment epithelium (RPE) layer of the retina. These vessels penetrate Bruch's membrane, destroying the retinal pigment epithelium, causing bleeding, and ultimately causing macular scarring (discal scarring) that results in severe loss of central vision.

[0261] In one embodiment, treatment of CNV with the compounds described herein reduces, slows or inhibits the development of abnormal blood vessels beneath the retinal pigment epithelium layer of the retina, slows or inhibits damage to Bruch's membrane, slows or inhibits the breakdown of the retinal pigment epithelium, and slows or inhibits scarring of the macular.

[0262] Retinal neovascularization occurs in a number of retinopathies associated with retinal ischemia, such as sickle cell retinopathy, Eales' disease, ocular ischemic syndrome, carotid-cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteriolaritis, radiation retinopathy, retinal vein occlusion, retinal artery occlusion, and retinal embolism. Retinal neovascularization also occurs in inflammatory diseases (e.g., birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, toxoplasmosis, uveitis), or other conditions, such as choroidal melanoma, chronic retinal detachment, incontinentia pigmenti, and rarely retinitis pigmentosa.

[0263] A common factor in almost all retinal neovascularization is retinal ischemia, which is believed to release diffusible angiogenic factors (e.g., VEGF). Neovascularization is initiated within the retina and then penetrates the inner limiting membrane. Neovascularization grows in the inner retina and posterior vitreous after the vitreous is detached (vitreous detachment). Neovascularization may originate from the optic disc or the surface of the retina. Retinal neovascularization generally progresses to vitreoretinal neovascularization. Iris neovascularization and neovascular glaucoma often occur after retinal neovascularization.

[0264] The therapeutic effect is measured by various evaluation items that are commonly used to evaluate intraocular neovascular disease. For example, visual acuity loss can be evaluated. Visual acuity loss can be evaluated, for example, but not limited to, by measuring the mean change in best corrected visual acuity (BCVA) from baseline to desired time point (e.g., where BCVA is based on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and evaluation at 4 meters test distance), measuring the percentage of subjects who lose less than 15 letters in visual acuity at desired time point compared to baseline, measuring the percentage of subjects who gain 15 letters or more in visual acuity at desired time point compared to baseline, measuring the percentage of subjects who have Snellen equivalent visual acuity of 20 / 2000 or worse at desired time point, measuring NEI visual function questionnaire, measuring the size of CNV and the amount of leakage of CNV at desired time point, for example, by fluorescein angiography. Eye evaluation can be performed, for example, but not limited to, by performing eye examination, measuring intraocular pressure, evaluating visual acuity, measuring slit lamp pressure, evaluating intraocular inflammation, etc.

[0265] Provided herein are methods of protecting the eye during medical procedures requiring exposure of the eye to bright light, laser light that results in prolonged and / or excessive pupil dilation or otherwise renders the eye sensitive to light, comprising administering to a patient in need thereof a composition comprising a compound as described herein.

[0266] In one embodiment, the medical procedure is ocular refractive surgery, corneal surgery, cataract surgery, glaucoma surgery, non-perforating glaucoma surgery, vitreoretinal surgery, global retinal photocoagulation, eye muscle surgery, ocular plastic surgery, laser therapy, or focal or grid laser photocoagulation. In one embodiment, the medical procedure is ocular refractive surgery. In one embodiment, the medical procedure is corneal surgery. In one embodiment, the medical procedure is cataract surgery. In one embodiment, the medical procedure is glaucoma surgery. In one embodiment, the medical procedure is non-perforating glaucoma surgery. In one embodiment, the medical procedure is vitreoretinal surgery. In one embodiment, the medical procedure is global retinal photocoagulation. In one embodiment, the medical procedure is eye muscle surgery. In one embodiment, the medical procedure is ocular plastic surgery. In one embodiment, the medical procedure is laser therapy. In one embodiment, the medical procedure is focal or grid laser photocoagulation.

[0267] In one embodiment, the composition is orally administered to a patient before or after a medical procedure.

[0268] In one embodiment, the composition is administered orally prior to a medical procedure, hi one embodiment, the composition is administered about 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 6 hours, 12 hours, or 24 hours prior to the procedure.

[0269] In one embodiment, the composition is administered after the medical procedure. In one embodiment, the composition is administered 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, or 48 hours after the medical procedure. In one embodiment, the composition is administered 24 hours after the medical procedure. In one embodiment, the composition is administered 48 hours after the medical procedure. In one embodiment, the composition is administered 24 hours and 48 hours after the medical procedure.

[0270] In one embodiment, the composition is administered as a single dose of the compound. In one embodiment, the composition comprises about 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or about 100 mg.

[0271] The compounds administered in such manner may be administered by any suitable means, such as those described herein and known in the art.

[0272] For the prevention or treatment of disease, the appropriate administration of the compounds will depend, in part, on the patient being treated, the severity and course of the disease, whether the compound is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's medical history and response to the compound, and the judgment of the attending physician. The compounds are suitably administered to the patient at one time or over a series of treatments.

[0273] The compositions can be administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The amount administered depends on the subject being treated and the capacity of the patient's immune system to utilize the active ingredient. Precise amounts of active ingredient required to be administered depend on the practitioner's judgment and are peculiar to each individual. Also, suitable regimes for initial administration and booster injections can be varied.

[0274] The compositions can be administered alone or in combination with a second treatment, either simultaneously or sequentially depending on the condition being treated. When more than one composition or composition and treatment is administered, the compositions or compositions / treatments can be administered in combination (sequentially or simultaneously). The compositions can be administered in a single dose or multiple doses.

[0275] The compounds described herein can optionally be administered in combination with one or more standard therapeutic treatments known in the art and described, for example, in more detail below.

[0276] Combination therapy Diabetic retinopathy results from the underlying diabetic condition, and further measures to reduce the risk of or slow its progression are to maintain optimal blood sugar levels; have regular and complete eye examinations; follow a healthy eating plan: eat different types of foods and eat the right amount of carbohydrates at each meal; exercise regularly; take medications exactly as prescribed; eat a low-fat and low-salt diet to keep cholesterol and blood pressure at normal levels; not smoke; keep blood pressure and cholesterol levels under control; and carefully monitor blood pressure during pregnancy.

[0277] Any of the methods described herein may be used in combination with one or more additional therapies, such as, but not limited to, laser treatment (e.g., focal laser photocoagulation or grid laser photocoagulation, or focal laser treatment or diffuse (panretinal) laser photocoagulation or diffuse laser treatment), cryotherapy, fluorescein angiography, vitrectomy, corticosteroids (e.g., intravitreal triamcinolone acetonide), anti-vascular endothelial growth factor (VEGF) treatment (e.g., pegaptanib (Macugen; Pfizer, Inc., New York, USA)), ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA), bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA). It will be appreciated that treatment with vitrectomy for persistent diffuse diabetic macular edema, pharmacological vitreous cord section in the management of diabetic retinopathy, fibrates, renin-angiotensin system (ras) blockers, peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, anti-protein kinase C (Ruboxistaurin), islet cell transplants; therapeutic formulations oligonucleotides, growth hormone and insulin growth factor (IGF), and systemic factor control may be combined.

[0278] The terms "co-administration," "administered in combination with," and grammatical equivalents, as used herein, are meant to encompass administration of a selected compound to a patient and include treatment regimens in which the compound is administered by the same or different routes of administration, or at the same or different times. In some embodiments, the compounds described herein are co-administered with another agent. These terms encompass administration of two or more compounds to a patient such that both compounds are present in the patient's body at the same time. These terms also encompass administration of a compound and a treatment (e.g., laser treatment) to a patient such that both compounds are present in the patient's body at the same time. These include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both compounds are present. Thus, in some embodiments, the compound and the other agent(s) / treatment are administered in a single composition or at a single time. In some embodiments, the compound and the other agent are mixed in a single composition.

[0279] Laser treatment Laser photocoagulation has been used since the 1960s to treat non-proliferative diabetic retinopathy, macular edema, and proliferative diabetic retinopathy.

[0280] Laser treatments are generally targeted to damaged eye tissue. Some lasers directly treat leaking blood vessels by "spot welding" and sealing the leaking area (photocoagulation). Other lasers remove abnormal blood vessels that form from neovascularization. Lasers can also be used to destroy the peripheral parts of the normal retina that are not involved in vision. This is done to preserve vision in the central part of the retina.

[0281] The two types of laser treatments commonly used to treat severe diabetic eye disease are:

[0282] Focal or grid laser photocoagulation or focal laser therapy This type of laser energy is either directed at the affected area or applied in a gentle grid-like pattern that is intended to destroy damaged eye tissue, eliminating areas of vision loss and scarring that contributes to vision loss. This method of laser treatment generally targets specific individual blood vessels.

[0283] This is the primary retinopathy laser treatment for macular degeneration from diabetic macular edema. The retinal laser seals the retinal blood vessels that are leaking fluid and blood. This in turn reduces the leakage of fluid and blood and reduces swelling of the macula. The retinal laser can also stimulate the retinal cells in some way to "pump" any excess fluid at the macula distally. The laser is only aimed at a specific portion of the macula; it does not touch the remaining peripheral retina.

[0284] The goal of retinal laser treatment is not to improve vision but to prevent it from worsening.

[0285] Panretinal Laser Photocoagulation or Diffuse Laser Therapy Panretinal photocoagulation is the first choice of treatment for proliferative diabetic retinopathy. It involves applying approximately 1,200 to 1,800 tiny spots of laser energy to the outermost (peripheral) area of ​​the retina, leaving the inner portion untouched. This laser treatment can shrink abnormal blood vessels. This treatment involves laser treatment of a large area of ​​the retina with the goal of coagulating or cauterizing ischemic retinal cells around the retina.

[0286] After pan-retinal laser, ischemic cells throughout the peripheral retina are replaced with scar tissue, which reduces the production of chemicals that stimulate the growth of abnormal new blood vessels. Diffuse laser treatment is usually performed over two or more appointments.

[0287] Laser surgery is often useful in treating diabetic retinopathy. To reduce macular edema, laser light is applied to the retinal lesion and seals leaking retinal blood vessels. For abnormal blood vessel growth (neovascularization), laser treatment is delivered to the peripheral retina. A small laser scar reduces abnormal blood vessel growth and helps attach the retina to the back of the eye, thus preventing retinal detachment. Laser surgery can significantly reduce the chance of severe vision loss.

[0288] cryotherapy Cryotherapy (coagulation) can aid in the treatment of diabetic retinopathy. If the vitreous is clouded with blood, laser surgery cannot be used until the blood has cleared or become clear. In some of these cases, retinal cryotherapy can be useful in shrinking the abnormal blood vessels and bonding the retina to the back of the eye.

[0289] Fluorescein angiography Fluorescein angiography has been useful as a research tool in understanding clinical pathological changes in the retinal circulation in eyes with diabetic retinopathy, and it has helped to classify diabetic retinopathy and predict its progression from baseline fluorescein angiography characteristics, especially the pattern of capillary nonperfusion.

[0290] This identifies sources of leakage in the periphery of the macula and guides laser treatment of macular edema. Fluorescein angiography may not be necessary for the treatment of proliferative diabetic retinopathy, but it can be useful in evaluating signs of retinal ischemia. In some cases, fluorescein angiography can identify neovascularization that would not otherwise be seen.

[0291] In patients with impaired glucose tolerance, fluorescein angiography can detect early retinal microvascular degeneration, indicative of early dysfunction of the blood-retinal barrier before diabetes becomes overt. These and other studies leave no doubt that fluorescein angiography can detect distinct early retinal vascular degeneration in diabetic patients without clinical retinopathy.

[0292] However, at present, the routine use of fluorescein angiography in the management of diabetic retinopathy should be guided by clinical experience, as there is little evidence to provide firm guidelines.

[0293] Vitrectomy Vitrectomy is the surgical removal of vitreous gel from the center of the eye and is often used in patients with advanced retinal disease. This procedure prevents complete detachment of the retina. It is commonly used to treat unremoved vitreous hemorrhage, vitreomacular traction, epiretinal membranes, and retinal detachment.

[0294] During a vitrectomy procedure, an operating microscope and small surgical instruments are used to remove blood and scar tissue associated with abnormal blood vessels in the eye. Removing the vitreous hemorrhage allows light to be focused again on the retina.

[0295] Vitrectomy often further prevents vitreous hemorrhage by removing the abnormal blood vessels that caused the bleeding. Removal of scar tissue encourages the retina to return to its normal position. Vitrectomy may be followed by laser treatment or may be performed simultaneously with laser treatment.

[0296] Vitrectomy, if performed early in people with vitreous hemorrhage, can reduce vision loss, especially if they also have severe proliferative retinopathy.

[0297] Conventional laser treatments may not be useful in eyes with vitreous hemorrhage or in eyes with tractional retinal detachment and actively progressing PDR. Early vitrectomy has been shown to improve visual recovery in patients with proliferative retinopathy and severe vitreous hemorrhage.

[0298] Refractive eye surgery Refractive eye surgery includes various methods of surgical reshaping of the cornea or cataract (e.g., radial keratectomy uses spoke-shaped incisions made with a diamond knife). In some cases, an excimer laser is used to reshape the curvature of the cornea. Refractive eye surgery can reduce or correct common vision disorders such as myopia, hyperopia, and astigmatism, as well as degenerative disorders such as keratoconus. Other types of refractive eye surgery include keratomileusis (removal of the corneal papilla, flash freezing, milling-grinding, and then restoring it to its original curvature), automated lamellar keratoplasty (ALK), laser-assisted myopia surgery (LASIK), intra-LASIK, laser-assisted subepithelial keratomileusis (LASEK aka Epi-LASIK), laser photorefractive keratectomy, laser thermal keratoplasty, conduction keratoplasty, limbal relaxing incisions, astigmatic keratotomy, radial keratotomy, mini asymmetric radial keratotomy, hexagonal keratotomy, lamellar keratoplasty, intracorneal rings or intracorneal ring implants (Intacs), contact lens implants, presbyopia inversion, anterior ciliary sclerotomy, laser inversion of presbyopia, scleral expansion bands, and Kamla inlay.

[0299] corneal surgery Examples of corneal surgery include, but are not limited to, corneal transplant surgery, penetrating keratoplasty, keratoprosthesis, therapeutic lamellar keratotomy, pterygium resection, keratochromasia, and odontogenic keratoprosthesis (OOKP). In some cases, corneal surgery does not require a laser. In other cases, corneal surgery uses a laser (e.g., therapeutic lamellar keratotomy, which removes superficial corneal opacities and surface irregularities). In some cases, patients are provided with sunglasses to protect their eyes from bright light after these procedures.

[0300] Cataract and Glaucoma Surgery Cataract surgery involves the surgical removal of the lens and its replacement with a plastic intraocular lens. Light is typically used to assist the surgeon.

[0301] Glaucoma surgery promotes the outflow of excess aqueous humor from the eye and reduces intraocular pressure. In some cases, these medical procedures use lasers (e.g., laser trabeculoplasty applies laser light to burn areas of the trabecular meshwork located near the base of the iris, increasing fluid outflow; laser peripheral iridotomy applies laser light to selectively burn holes near the base of the iris periphery; etc.). Schlemm's canaloplasty is an advanced non-penetrating procedure that utilizes microcatheter technology in a simple and minimally invasive procedure, designed to promote drainage through the eye's natural drainage system. Other medical procedures used to treat glaucoma include lasers, non-penetrating surgery, protective filtration surgery, and drainage valve implantation.

[0302] Corticosteroids (intravitreal triamcinolone acetonide) Corticosteroids reduce vascular permeability and attenuate blood-retinal barrier dysfunction by inhibiting VEGF gene transcription and translation and leukocyte adhesion to the vascular wall. Corticosteroids specifically address complications associated with increased vascular permeability.

[0303] Intravitreal triamcinolone acetonide (IVTA) (4 mg) was useful in reducing the risk of progression of diabetic retinopathy. However, the study concluded that the use of IVTA to reduce the likelihood of progression of retinopathy is not warranted at this time because of the increased risk of glaucoma and cataracts associated with IVTA and because PDR can already be successfully and safely treated with extensive retinal photocoagulation.

[0304] Several small randomized clinical trials have found that the combination of IVTA and laser photocoagulation (pan-retinal and macular) is associated with improved best-corrected visual acuity and reduced central macular thickness and total macular volume compared with the use of laser photocoagulation alone for the treatment of PDR and macular edema. However, a recent study showed that the combination of IVTA with extensive retinal and macular photocoagulation in eyes with coexisting high-risk proliferative diabetic retinopathy (PDR) and clinically significant macular edema was not beneficial when compared with extensive retinal and macular photocoagulation as standard of care in these patients.

[0305] Anti-vascular endothelial growth factor (VEGF) treatment Currently, there are four anti-VEGF agents used in the management of diabetic retinopathy, including pegaptanib (Macugen; Pfizer, Inc., New York, USA), ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA), bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA).

[0306] Pegaptanib is a pegylated RNA aptamer against the VEGF-A 165 isoform. A phase II clinical trial of intravitreal pegaptanib in patients with DME with 36-week follow-up showed better visual outcome, reduced central retinal thickness, and reduced need for further photocoagulation therapy. A retrospective analysis of a similar study in patients with baseline retinal neovascularization showed regression of neovascularization after administration of intravitreal pegaptanib. A recent retrospective study found that repeated use of intravitreal pegaptanib significantly improved best-corrected visual acuity and reduced mean central macular thickness in patients with diabetic macular edema.

[0307] Ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF-A. Preliminary studies of intravitreal ranibizumab have shown a reduction in foveal thickness and maintenance or improvement of visual acuity in patients with DME. Recently, Nguyen et al. (2009) found that repeated intravitreal injections of ranibizumab over a 6-month period produced significantly better visual outcomes than topical / grid laser treatment in patients with DME. The Diabetic Retinopathy Clinical Investigation Network (2010a) evaluated intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone in combination with topical / grid laser compared with topical / grid laser alone for the treatment of diabetic macular edema. Nguyen et al. (2010) showed in a randomized trial that intraocular injections of ranibizumab provided benefit for diabetic macular edema for at least 2 years and, when combined with topical or grid laser treatment, reduced the amount of residual edema, as did the number of injections required to control the edema.

[0308] VEGF Trap is a 115 kDa recombinant fusion protein consisting of the VEGF-binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human IgG1. In one preliminary study, a single intravitreal injection of VEGF Trap-Eye was well tolerated and demonstrated efficacy in patients with diabetic macular edema.

[0309] Bevacizumab is a full-length recombinant humanized antibody active against all isoforms of VEGF-A. It is approved by the FDA as adjunctive systemic treatment for metastatic colorectal cancer. Several studies have reported the off-label use of intravitreal bevacizumab (IVB) for the treatment of diabetic macular edema (DME), complications of proliferative diabetic retinopathy (PDR), and iris neovascularization. Several studies have also demonstrated that IVB injections caused significant regression of retinal and iris neovascularization and rapid resolution of vitreous hemorrhage in patients with proliferative diabetic retinopathy (PDR). Furthermore, IVB injections have been shown to be an effective adjunct to PRP in the treatment of high-risk proliferative diabetic retinopathy (PDR) and neovascular glaucoma. Short-term results suggest that IVB has the potential to prevent retinal thickness expansion as well as reduce retinal thickness after cataract surgery in eyes with diabetic macular edema (DME).

[0310] Vitrectomy for persistent diffuse diabetic macular edema Vitrectomy, which removes the premacular posterior hyaloid membrane, for persistent diffuse macular edema (DME) has rapidly gained widespread acceptance. Many serial evaluations of the efficacy of vitrectomy (with or without internal limiting membrane peeling) have yielded conflicting results. Results have observed that vitrectomy with internal limiting membrane peeling outperforms eyes with persistent diffuse diabetic macular edema (DME) that have not responded to prior conventional laser treatment and that are certainly affected in distance and reading visual acuity as well as edema morphology. Another study suggested that vitrectomy with or without internal limiting membrane peeling may provide anatomic and visual benefits in eyes with diffuse nontractional unresponsive diabetic macular edema (DME) that is refractory to laser photocoagulation.

[0311] Another study found that the benefit of vitrectomy for diabetic macular edema (DME) in terms of visual acuity and macular thickness was limited for patients who showed signs of macular traction, either clinically and / or optical coherence tomography.

[0312] Pharmacological vitreous cord section in the management of diabetic retinopathy Upon demonstration, intravitreal injection of microplasmin with combined induction of posterior vitreous detachment (PVD) and vitreous liquefaction was observed to increase intravitreal oxygen tension. On the other hand, hyaluronidase-induced vitreous liquefaction without PVD induction did not increase intravitreal oxygen tension. Furthermore, when microplasmin-treated animals were exposed to 100% oxygen, the increase in oxygen levels in the vitreous cavity was accelerated compared to control or hyaluronidase-treated eyes. These findings suggest that the beneficial effect of surgical vitrectomy in increasing oxygen tension in the vitreous cavity can be reproduced by enzymatic induction of PVD and vitreous liquefaction, without the time, risks and costs of surgery. In 2009, it was shown that intravitreal injection of autologous plasmin enzyme without vitrectomy induces complete PVD, effectively reduces macular thickening caused by refractory diffuse diabetic macular edema, and improves visual acuity. Therefore, traumatic pharmacological separation of the posterior vitreous cortex, which completely cuts between the internal limiting membrane and the posterior hyaloid membrane without vitrectomy, can reduce the risk of iatrogenic damage during surgery such as retinal breaks, damage to nerve fibers, and postoperative sequelae.

[0313] Fibrates Fibrates are lipid-lowering drugs that are widely prescribed for the treatment of dyslipidemia. Their main clinical effects, mediated by the activation of peroxisome proliferator-activated receptor alpha, are a modest reduction in total cholesterol and low-density lipoprotein cholesterol concentrations, a significant reduction in triglycerides, and an increase in high-density lipoprotein cholesterol. The Fenofibrate Administration and Event Reduction in Diabetes (FIELD) study showed that long-term lipid-lowering therapy with fenofibrate inhibits the progression of diabetic retinopathy and reduces the need for laser treatment in patients with type 2 diabetes, although the mechanism of this effect does not appear to be related to the plasma concentration of lipids. Recently, the ACCORD study group (2010) showed that fenofibrate for intensive treatment of dyslipidemia inhibits the rate of progression of diabetic retinopathy in people with type 2 diabetes.

[0314] Renin-angiotensin system (RAS) blockers Several studies suggest that RAS blockade can reduce the burden of diabetic retinopathy. Findings from the Eurodiab Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) suggest that blockade of the renin-angiotensin system with the angiotensin-converting enzyme inhibitor lisinopril can reduce both the incidence and progression of retinopathy in type 1 diabetes. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists

[0315] The PPARγ agonist rosiglitazone inhibited both retinal leukocyte adhesion and retinal leakage observed in experimental diabetic rats. Furthermore, reduced expression of endogenous PPARγ in mice exacerbated retinal leukocyte adhesion and retinal leakage in diabetic mice. Rosiglitazone maleate (Avandia; GlaxoSmithKline, North Carolina, USA) is an orally administered drug used to improve glycemic control in diabetic patients. The drug activates PPARγ, resulting in insulin sensitization in adipose and other tissues with potential antiangiogenic activity.

[0316] Anti-protein kinase C (ruboxistaurin) PKC influences several ocular complications of diabetes, it is activated by VEGF, and it is a promising target for the treatment of diabetic retinopathy.

[0317] Ruboxistaurin (RBX) is an oral PKCβ inhibitor, a selective inhibitor with adequate bioavailability to allow once-daily oral dosing. In the Protein Kinase C β inhibitor-Diabetic Retinopathy Study 2 (PKC-DRS2), oral administration of RBX (32 mg per day) improved the achievement of visual improvement while reducing persistent slow visual loss, the need for laser treatment for macular edema, and progression of macular edema in patients with nonproliferative retinopathy.

[0318] islet cell transplantation Recent studies have observed improvements in islet transplant outcomes through accelerated islet isolation, glucocorticoid-free immunosuppression, and provision of adequate islet doses of more than 10,000 islet equivalents per kg of body weight, which have led to benefits for type 1 diabetes patients, such as prolonged C-peptide secretion, improved glycemic control, and fewer hypoglycemic episodes.

[0319] Therapeutic Oligonucleotides Oligonucleotides represent one of the new therapeutic entities that target specific relevance in disease processes. There are two main categories of oligonucleotide therapeutics: antisense oligonucleotides, e.g., small interfering RNA (siRNA), and oligonucleotide aptamers.

[0320] Antisense oligonucleotides are novel therapeutic agents designed to bind to specific messenger RNA (mRNA), which degrades the message encoding the targeted protein, affecting reduced production of the specific protein associated with the target disease. Delivery of antisense oligonucleotides by intravitreal injection is a rational therapeutic approach in the treatment of retinal diseases. Alternative options for drug delivery of antisense and other oligonucleotides have been under investigation, including periorbital administration, iontophoresis, and sustained release formulations.

[0321] Growth hormone and insulin growth factor (IGF) Growth hormone and insulin growth factor (IGF) modulate the function of retinal endothelial progenitor cells and activate hypoxia-induced retinal neovascularization; IGF 1 can also disrupt the blood-retinal barrier and increase retinal vascular permeability.

[0322] Intravitreal hyaluronidase Intravitreal sheep hyaluronidase injections are effective in clearing vitreous hemorrhage. Several human case series have shown that intravitreal injections of autologous plasmin enzyme are a safe and effective adjunct to vitreous surgery to treat diabetic macular edema and proliferative diabetic retinopathy.

[0323] Control of systemic factors: Primary prevention of diabetic retinopathy involves strict glycemic, lipid and blood pressure control. Some of the systemic factors that should be controlled to prevent diabetic retinopathy are detailed below.

[0324] Blood sugar control Hyperglycemia triggers a cascade of events that ultimately lead to the development of diabetic retinopathy. Therefore, one of the treatments that can be used to slow the progression of diabetic retinopathy is glycemic control. Glycemic control reduces the risk of developing and inhibits the progression of diabetic retinopathy in both type 1 and type 2 diabetes.

[0325] Blood pressure control Hypertension exacerbates diabetic retinopathy by increasing blood flow and mechanical damage (stretching) of vascular endothelial cells, stimulating the release of VEGF. Tight blood pressure control reduces the risk of progression of retinopathy by about one-third, the risk of vision loss by half, and the need for laser treatment by one-third in people with type 2 diabetes. Blood pressure control can also reduce the onset and progression of diabetic retinopathy.

[0326] Serum lipid control Dyslipidemia is involved in the pathogenesis of diabetic retinopathy. The severity of retinopathy was associated with increased triglycerides and inversely with HDL cholesterol. Hydroxymethylglutaryl coenzyme A (HMG CoA) inhibitors may be useful in the management of diabetic retinopathy (DR) and diabetic macular edema (DMO) in patients with dyslipidemia. EXAMPLES

[0327] The present application can be better understood by reference to the following non-limiting examples. The following examples are presented to more fully illustrate representative embodiments, but they should not be construed as limiting the broad scope of the present application.

[0328] The term ACU-4429 relates to the compound (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol. The term ACU-4935 relates to the compound (R)-3-amino-1-(3-(2-propylpentyloxy)phenyl)propan-1-ol.

[0329] (Example 1) Accepted animal models of diabetic retinopathy Mice, rats, dogs, cats, and monkeys are some of the common animal models used to study diabetic retinopathy.

[0330] Animal studies are crucial for understanding the pathogenesis of retinopathy because systematic structural, functional and biochemical studies cannot be undertaken in human subjects. Animal studies are of great importance in attempts to develop adjuvant therapeutic strategies. Retinal lesions characteristic of diabetes have been successfully reproduced in diabetic or galactose-fed laboratory animals.

[0331] Data obtained from cell culture assays and animal studies can be used in determining a range of dosages for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. Dosages can vary within this range depending on the dosage form used and the route of administration utilized. For any compound used in the methods of the invention, a therapeutically effective dose can be initially estimated from cell culture assays. Dosages can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves half-maximal inhibition) determined in cell culture. Levels in plasma can be measured, for example, by high performance liquid chromatography. Such information can be used to more accurately determine useful doses in humans.

[0332] Some of the common animal models for studying diabetic retinopathy are detailed below, along with source and related texts.

[0333] mouse Protocols that can be used to test compounds for therapeutic efficacy in mice include, for example, those described in Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009; Kern et al., (Arch Ophthalmol. 1996;114(8):986-990); Feit-Leichman et al. (Investigative Ophthalmology & Visual Science, 46(11): 4281-4287, November 2005).

[0334] Rat Protocols that can be used to test compounds for therapeutic efficacy in rats include, for example, those described in Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009; Sima et al. (Current Eye Research, 1985, Vol. 4(10) Pages 1087-1092); Kato et al. (Journal of Diabetes and Its Complications, Volume 17(6): 374-379, November 2003); Sima et al. (Metabolism, 32(7, Suppl. 1): 136-140, July 1983); Lu et al. (Journal of Ophthalmology, 47(1): 28-35, 2003); and Deng et al. (International Journal of Diabetes, vol. 6 (issue 1), 1998).

[0335] Hamsters and other rodents Protocols that can be used to test compounds for therapeutic efficacy in hamsters and other rodents include, for example, those described in Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009.

[0336] Dogs Protocols that can be used to test compounds for therapeutic efficacy in dogs include, for example, those described in Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009; Engerman et al. (Arch Ophthalmol. 1995; 113(3):355-358); and Kador et al. (Arch Ophthalmol. 1990; 108(9):1301-1309).

[0337] Cat Protocols that can be used to test compounds for therapeutic efficacy in cats include, for example, those described in Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009; Mansour et al. (Investigative Ophthalmology & Visual Science, Vol. 31, No. 3, March 1990); and Henson and O'Brien (ILAR Journal Volume 47(3): pp. 234-242).

[0338] Monkeys and primates Protocols that can be used to test compounds for therapeutic efficacy in monkeys and primates include, for example, those described in Kim et al. (Invest Ophthalmol Vis Sci. 2004;45:4543-4553); Akimba: A Novel Murine Model for Diabetic Retinopathy (www.Bio-link.com); and Diabetic Retinopathy by Elia Duh, Springer, Humana Press, 2009.

[0339] (Example 2) Use of Compounds for Treating Diabetic Retinopathy - Patent application A single-center, open-label, dose-escalation pilot study is being initiated to determine the biological activity of oral administration of the compounds described herein in patients with clinically significant diabetic macular edema (DME) involving the central macula, and to report any associated adverse events. Patients with DME involving the central macula and best corrected visual acuity (BCVA) between 20 / 63 and 20 / 400 in the study eye will be enrolled.

[0340] Eligible patients will be randomly assigned in a 1:1 ratio to receive daily oral doses of the compound (2 mg, 5 mg, 7 mg, 10 mg, or 20 mg) administered through Month 24. The primary endpoints are the frequency and severity of ocular and systemic adverse events. Secondary endpoints are 1) best corrected visual acuity assessed with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart using a standardized refraction and testing protocol with a starting test distance of 2 m, and 2) measurement of retinal thickness by optical coherence tomography. The adjudicating physician will be blinded to the patient's treatment assignment, and the physician administering the dose will be aware of the patient's treatment assignment, either test or sham, but will be blinded to the dose of the compound. Other personnel at each study site, the patients, and personnel at the central reading center will be blinded to the patient's treatment assignment.

[0341] Efficacy analyses will be performed on an intention-to-treat basis among all patients using the last-observation-carried-forward (LOCF) method for missing data. For all pairwise comparisons, statistical models will be adjusted for baseline visual acuity score (<55 letters vs. ≥55 letters). Between-group comparisons for dichotomous endpoints will be performed using the Cochran chi-square test. Changes from baseline visual acuity will be analyzed using an analysis of variance model. For lesion characteristic endpoints, an analysis of covariance model adjusting for baseline values ​​will be used. For the primary endpoint, the Hochberg-Bonferroni multiple comparison procedure will be used to adjust for the two pairwise treatment comparisons. Safety analyses will include all patients treated.

[0342] The compound is expected to be a well-tolerated treatment for patients with DME and may have the potential to maintain or improve best corrected visual acuity and reduce retinal thickness in patients with clinically significant DME, including central DME.

[0343] (Example 3) Manganese-enhanced magnetic resonance imaging (MEMRI) protocol Prior to the start of the experimental period, rats are maintained under normal laboratory lighting (12 hours light, 12 hours dark). Light exposure, bleaching, and dark adaptation are varied by cohort (see below).

[0344] Animals are dosed by oral gavage according to group allocation below. Rats are weighed each week of the experimental period.

[0345] 10-30 min prior to photobleaching, a drop of tropicamide is instilled into the eye to dilate the pupils. Four hours prior to MRI imaging, animals are photobleached by exposure to 5000 lux for 10 min.

[0346] Rats are injected immediately after bleaching, 4 hours before the start of the imaging session. The MEMRI signal reflects the state of expression of activity-dependent channels during the duration of the experiment.

[0347] Awake rats are injected intraperitoneally with MnCl2 into the lower abdomen.

[0348] MnCl2 is injected at 60 mg / kg using a stock solution of 20 mg / mL.

[0349] Each injected rat is marked and the injection, time of bleaching, start and end of imaging, and light conditions are recorded in a notebook.

[0350] For experimental runs for all groups except group 4, rats are kept in the dark (IOP room) for 4 hours between injection and transport to the imaging center. Group 4 animals are exposed to light for 4 hours between MnCl2 injection and MRI imaging. Otherwise, the light-dark-bleach cycle described is followed for each cohort.

[0351] Rats will be transported to the imaging center via an IACUC approved route immediately following the light-dark cycle for each cohort.

[0352] Depending on the particular experiment, both or one eye of each rat is imaged.

[0353] MRI parameters include the following:

[0354] A snapshot FLASH inversion recovery (IR) imaging sequence is used to obtain a single imaging slice that bisects the retina in the axial and sagittal planes using a 12 mm inner diameter linear surface coil. Imaging parameters are TR / TE=1000 / 2.7 ms and 125 ms inversion time (TI), sweep width=73.5 kHz, number of acquisitions=120; slice thickness=0.7 mm, field of view=12 mm×12 mm, and a 256×256 data matrix resulting in an in-plane resolution of 47 microns. Approximate scan time per animal is about 16 min.

[0355] The total time required to image one eye (including setup and scout imaging) is approximately 1 hour. If the animal moves, it is re-imaged.

[0356] (T1 mapping): Determined optimal during protocol progression A snapshot FLASH inversion recovery (IR) imaging sequence was used to obtain a single imaging slice that bisects the retina in the axial and sagittal planes using a 12 mm inner diameter linear surface coil. Imaging parameters were TR / TE=2000 / 2.7 ms, sweep width=73.5 kHz, number of acquisitions=32; slice thickness=0.7 mm, field of view=12 mm×12 mm, and a 192×192 data matrix (zero padded to 256×256) resulting in an in-plane resolution of 47 microns. Signals acquired at six inversion times [TI=50, 150, 300, 400, 900, 1800 ms] were used to obtain T1 maps.

[0357] Wait until the animal has recovered from anesthesia before transporting. Use a heat lamp after imaging to help maintain body temperature while the animal is recovering from anesthesia.

[0358] cohort [Table 1]

[0359] Study design The time series for groups 1-3 are shown in Figure 1.

[0360] The time series for group 4 is shown in FIG.

[0361] The time series for groups 5 and 6 are shown in FIG.

[0362] Single-dose study The purpose of this study was to determine whether a single (high) dose of ACU-4429 significantly increased retinal cationic activity (Mn 2+ The objective of this study was to determine whether ACU-4429 reduces the uptake of Mn in the retina. Groups 1-4 (ACU-4429 vs. vehicle) are dosed and placed under room light for 2 hours. Groups 5 and 6 (retinyl acetamide vs. vehicle) are dosed 18 hours prior to bleaching. The animals have their pupils dilated and are exposed to moderate white light (5,000 lux diffuse white fluorescent light) for 10 minutes, which allows for bleaching. Immediately after bleaching, the animals are dosed with Mn 2+Intraperitoneally (IP) injection of Mn was performed followed by 4 hours of dark adaptation (animals were left dark adapted while waiting for imaging). Group 3 animals were left under ambient room light, which acted as a dimming light (the hope is that the retinyl acetamide and ACU-4429 treatment will cause the retina to behave as if it were light adapted). MRI imaging (30 min to 1 h per animal) was performed with Mn 2+ Imaging is performed 4 hours after injection (ip) and in the same light conditions that the animals were in prior to imaging. Dosing of the animals is staggered to ensure that the time from dosing to imaging is the same for all animals.

[0363] Repeated dose study The purpose of this study was to determine whether repeated treatment with ACU-4429 (10 mg / kg / day) in normal cyclic light over time would result in increased retinal cationic activity (Mn 2+ The aim of the study was to test whether ACU-4429 reduces the uptake of Mn in mice. There were three groups: Group 1: 5 mg / kg (10 mg / kg / day) twice daily; Group 2: vehicle (dark adapted); Group 3: vehicle (room light). All treatments were administered under normal cyclic light exposure (12 hours of diffuse white fluorescent light at approximately 100 lux) for 6 days, with the lights on and off. Immediately after the morning treatment on the 7th day, a drop of atropine sulfate (1%) was instilled into both eyes of all animals to dilate the pupils. Six hours after the administration of the final dose and at least 6 hours in normal light, Group 1 (ACU-4429) and Group 2 (dark adapted) were administered Mn 2+ After IP injection of Mn, animals were allowed to dark adapt for 4 hours (animals were left dark adapted while awaiting imaging), and groups 1 and 2 were imaged in the dark (30 min to 1 hour per animal). Six hours after the final dose, group 3 (room light) was injected with Mn 2+ IP and group 3 is left under normal room light for an additional 4 hours before imaging. Imaging of group 3 is performed under normal light.

[0364] (Example 4) Reduction of oxygen-induced retinopathy in rats Objective: Test compounds are evaluated in rats with oxygen-induced retinopathy (OIR), a common model of human retinopathy of prematurity (ROP). Both OIR and ROP are characterized by abnormalities in the retinal vasculature and long-term dysfunction of the neural retina.

[0365] Methods: OIR is induced in Sprague-Dawley rat pups (N=24) from 4 litters by exposure to alternating periods of 50% and 10% oxygen from the day of birth (P0) through P14. The light cycle is 12 hours light (10-30 lux) and 12 hours dark, with the light-dark transition occurring simultaneously with each oxygen shift. From P7 through 15 days, pups from litters 1 and 4 are orally dosed with 6 mg / kg of the clinical development candidate within 1 hour of this transition, whereas pups from litters 2 and 3 receive vehicle only. Electroretinograms are recorded from P20-22, when prominent retinal vascular abnormalities are typically observed, to determine receptor and post-receptor function. Treatment effects are determined by ANOVA.

[0366] Assessment: The maximum rod response and the amplification constant of light signaling are assessed following treatment with the clinical candidate. Additionally, the time constant of inactivation of light signaling is assessed using a double flash protocol. Post-receptor sensitivity (log s) and maximum dark-adapted b-wave amplitude are also assessed. Changes in photoreceptor response following treatment with the clinical candidate may also be assessed, as well as responses arising from the inner retina. The inner retina is supplied by the retinal vasculature, and quantitative image analysis of fundus photographs is used to determine the degree of vascular abnormalities associated with OIR following such treatment. It is expected that the degree of vascular abnormalities will be reduced in animals treated with the clinical candidate.

[0367] (Example 5) Visual cycle regulation and rod function in a rat model of ROP The rat model of ROP provides a convenient in vivo system in which the relationship between photoreceptors and the retinal vasculature can be studied and manipulated.

[0368] Both OIR and ROP are characterized by long-term dysfunction of the neural retina and abnormalities in the retinal vasculature. The systemic effects of a clinical development candidate, a regulator of the visual cycle, will be studied in rats with oxygen-induced retinopathy (OIR).

[0369] Retinopathy is induced in Sprague-Dawley rat pups (N=24) by alternating 24-hour exposures to 50±1% and 10±1% oxygen from the day of birth through postnatal day (P) 14. The light cycle is controlled at 12 hours, 10-30 lux and 12 hours of darkness, except during the test day, when constant darkness is maintained. The transition from light to dark is timed to occur simultaneously with each oxygen alternation.

[0370] During this transition, starting on P7 for 2 weeks, pups from litters 1 and 4 are orally dosed with 6 mg / kg of the clinical development candidate, while pups from litters 2 and 3 receive an equal volume of vehicle only (20% dimethylsulfoxide (DMSO)). The dosing schedule is designed to continue over the age range beginning with the onset of a rapid increase in retinal rhodopsin content and continuing until rhodopsin content exceeds 50% of the adult amount (Fulton and Baker, Invest Ophthalmol Vis Sci (1984) 25:647).

[0371] Treated rats remain in room air (20.8% oxygen) for approximately 20 minutes between each oxygen change from P7 to P14. Rats are evaluated according to a longitudinal design with tests at P20-22, P30-32, and P60-62. These days are chosen because they capture the apex of vascular abnormalities, the period of significant recovery, and the age of maturation, respectively. At each test age, neuroretinal function and morphology of the retinal vasculature are assessed using non-invasive techniques.

[0372] Shortly after the last dose (0-2 days), the effects of the compounds are assessed in the neural retina by electroretinograms (ERGs). The timing and intensity of the stimulation, designed to assess rod photoreceptor and rod-mediated post-receptor neuronal function, is computer controlled. Two sets of experiments are performed. The first evaluates rod and rod-mediated neuronal function in the dark-adapted retina. The second evaluates rod photoreceptor recovery from a strong light stimulus that bleaches rhodopsin. Each set of experiments is performed in approximately half of the patients from each litter.

[0373] To assess whether VCM treatment affects the retinal vasculature, comprehensive images of the fundus are obtained showing the major vessels of the retina after each ERG session. Images are composited to show an overview of the posterior pole, i.e., the area within the circle wrapped around the vortex vein and concentric with the optic disc, as shown in Figure 19, and the retinal region that is most important for diagnosing high-risk ROP in human patients. Arterioles are analyzed with RISA custom image analysis software (Gelman, Invest Ophthalmol Vis Sci (2005) 46: 4734).

[0374] (Example 6) Animal models of laser-induced choroidal neovascularization and macular degeneration Murine model of choroidal neovascularization The efficacy of the VCM compounds described herein can be evaluated in a murine model of choroidal neovascularization.

[0375] Briefly, 4-5 week old C57BL / 6 mice are anesthetized with ketamine:xylazine hydrochloride (100 mg / kg:10 mg / kg) and pupils are dilated with 1% tropicamide (Alcon Laboratories, Inc Fort Worth, TX). Three 532 nm diode laser photocoagulation (75 pm spot size, 0.1 sec duration, 120 mW) burns are delivered to each retina using the slit lamp delivery system of a photocoagulator (OcuLight; Iridex, Mountain View, CA) and a hand-held cover slide as a contact lens. Burns are delivered at the 9 o'clock, 12 o'clock, and 3 o'clock locations of the posterior pole of the retina. The generation of air bubbles during laser delivery indicates disruption of Bruch's membrane and is a key factor in obtaining CNV, therefore only burns generating air bubbles are included in this study.

[0376] Four separate experiments are conducted to investigate the efficacy of the clinical development candidate when administered orally on day 0 after disruption of Bruch's membrane. Mice in groups 1-4 are orally administered daily doses of the clinical development candidate at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg, respectively. Group 4 receives vehicle only.

[0377] After 14 days, mice were anesthetized and injected with fluorescein-labeled dextran (2 × 10 6Choroidal flat mounts are prepared by perfusion of the eyes with 10% phosphate-buffered formalin (average molecular weight 0.01 mg / ml, Sigma-Aldrich). Briefly, eyes are enucleated and fixed in 10% phosphate-buffered formalin for 1 h, and the cornea and lens are removed. The entire retina is carefully dissected from the eyecup, quarters are cut from the edge of the eyecup to the equator, and the retina is flat-mounted in aqueous mounting medium (Aquamount; BDH, Poole, UK). Flat mounts are examined under a fluorescence microscope (Axioskop; Carl Zeiss Meditec, Thornwood, NY) and images are digitized with a 3-charge-coupled device (CCD) color video camera (1K-TU40A, Toshiba, Tokyo, Japan). The area of ​​each CNV lesion is measured using frame-grabbing image analysis software. Statistical comparisons are made using ANOVA with Dunnett's correction for multiple comparisons.

[0378] Murine model for inhibition of choroidal neovascularization Although animals do not develop age-related macular degeneration (AMD) per se, choroidal neovascularization similar to that seen in AMD can be produced by using a laser to produce localized destruction in Bruch's membrane and the overlying retinal pigment epithelium (RPE). This damage stimulates abnormal growth of the underlying choroidal capillaries into the RPE layer and the subretinal space. Destruction of Bruch's membrane is common to all forms of choroidal neovascularization (CNV), including that which characterizes wet AMD.

[0379] In the laser-induced choroidal neovascularization model, mice in Group 9 or Group 10 are either (1) treated with an oral dose of the clinical development candidate or (2) sham-treated 1 day prior to laser injury, and 2, 5, 8, and 11 days after laser injury. 14 days after laser injury, mice are injected intravenously with fluorescein-labeled dextran (50 mg), euthanized, and eyes are either quickly dissected for choroidal flat mounts or frozen in optimal cutting temperature embedding compound and sectioned for lesion assessment.

[0380] CNV lesions are visualized by fluorescein angiography and graded according to standard procedures.

[0381] (Example 7) Efficacy study in chronic light-induced choroidal neovascularization Objective: The objective of this study was to test the efficacy of 3 months (90 days) of once-daily oral treatment with clinical development candidates at 0.3 and 3 mg / kg / day for protection from 3000 lux light damage in vivo using Wistar rats. Prolonged light damage (3 months) in rats has been shown to result in photoreceptor degeneration and choroidal neovascularization (CNV). The efficacy of exemplary clinical development candidates in protecting against light-induced ONL and CNV was determined.

[0382] Materials and Methods: The day before dosing began and once a week for 13 weeks, the clinical development candidates were weighed and placed into unused, empty glass scintillation vials. The clinical development candidates were dissolved in deionized water to the concentration required to achieve the desired dosing in the desired dosing volume (0.5 mL / animal). The dosing solution was stored at 4° C. and used for dosing once daily for one week. The vehicle used for the dosing control group was deionized water. Sixteen female Wistar rats (Charles River Laboratories) were used for this study. The animals had an average body weight of 220 grams and were approximately 12 weeks old at the start of dosing.

[0383] Assay: Animals were orally gavaged once daily in the morning (within 1 hour of light onset) with assigned vehicle control or test article using a 1 mL syringe fitted with a 20-gauge gavage needle. The animals were kept under cyclic lighting with 12 hours of 3000 lux white light in the center of the cage alternating with 12 hours of darkness. Upon completion of the study, animals were euthanized with carbon dioxide followed by pneumothorax. Immediately after cervical dislocation, both eyes of the animals were removed for analysis. Analysis consisted of staining of sections and flat-mount analysis. Eyecups were fixed in 4% PFA for 1 hour at room temperature. One eyecup was processed for paraffin embedding, sectioned, and stained with H&E or isolectin B4. The other eye was fixed for flat-mounting. Flat-mounted eyes were dissected into retina and choroid / sclera complex. Both the retina and the choroid / sclera complex were stained with isolectin B4.

[0384] research design [Table 2]

[0385] Data Analysis: Eye sections were examined microscopically after H&E staining and the ONL area near the optic nerve was photographed at 40x10x for outer nucleated cell count. Photomicrographs were printed on 8"x11" paper. The number of ONL nuclei evenly distributed on the photograph where two perpendicular lines intersect was counted and the average cell count represents the ONL thickness for that eye. Paraffin sections were stained with isolectin B4 to determine whether choroidal neovascularization was present. Isolectin B4 stains blood vessels (see Figure 16). To quantify choroidal neovascularization, the number of blood vessels traversing the retina from the choroid was counted per section and analyzed in Excel. Blood vessels were counted in 10-33 sections and data reported as the average per animal. Flat mount data were excluded from this report as they were inconclusive.

[0386] conclusion [Table 3]

[0387] Figure 22 shows the number of nuclear rows in the outer nuclear layer of H&E sections from animals treated with ambient light and vehicle or 3000 lux per clinical development candidate. Data are mean ± SEM. [Table 4-1] [Table 4-2]

[0388] FIG. 23 shows the number of blood vessels crossing the layer or section. Results: The clinical development candidate protects the retina from light-induced ONL thickness loss. Treatment with the clinical development candidate provided significant protection against choroidal neovascularization.

[0389] (Example 8) A Phase I Dose-Ranging Study of ACU-4429, a Novel Visual Cycle Modulator, in Healthy Volunteers Visual cycle regulation (VCM) refers to the biological conversion of photons into electrical signals in the retina (see Figures 4A and 4B).

[0390] The retina contains photoreceptor cells known as "rods" (responsible for night vision) and "cones" (responsible for day vision). Rod cells are much more numerous and active than cone cells. Overactivity of rods can cause a buildup of toxins in the eye, but cones provide the majority of our visual information, including color. VCM essentially "slows down" the activity of the rods, reducing the metabolic load on the cones.

[0391] Isomerase / RPE65 is one target for inhibition because it is specific to the visual cycle. Rod cells are the major source of A2E (90% of photoreceptor cells).

[0392] A2E toxicity · Production of free radicals upon exposure to light; Detergent-like properties can damage the RPE cell membrane; RPE lysosomal inhibition (leading to drusen formation); and Activation of complement factors.

[0393] ACU-4429 was designed to prevent or inhibit the production of toxic by-products of the visual cycle that can lead to degenerative conditions in the eye. ACU-4429 is administered to patients as an oral pill taken daily, rather than by injection into the eye. Preclinical data shows that ACU-4429 slows down the rod visual cycle.

[0394] Phase 1 data Safety and tolerability were observed in healthy volunteers aged 55 to 80 years. Dose-dependent modulation of the visual cycle was monitored by electroretinogram (ERG).

[0395] Clinical safety and tolerability ACU-4429 was administered to 125 healthy subjects. ACU-4429 was well tolerated in these healthy subjects with no DMC-related AEs. Headaches were observed in some subjects, but were transient and likely unrelated to the drug. Mild and transient visual AEs were observed. ACU-4429 produced a very good pharmacological response, even at low doses. No changes were observed in the cone ERG.

[0396] Overall, ACU-4429 has oral bioavailability. Dose vs. AUC and C max A linear correlation exists between the dose and the ERG b-wave amplitude, reaching a plateau after the first dose. A dose-dependent decrease in the ERG b-wave amplitude was observed.

[0397] The AUC increased approximately proportionally with dose, and thus systemic exposure can be easily adjusted in the clinic by increasing or decreasing the oral dose of ACU-4429. max) also increased linearly with dose. ACU-4429 was rapidly absorbed from the GI tract (see FIG. 7). Phase 1a rod ERG inhibition of ACU-4429 (24 hours) is shown in FIG. 6. [Table 5-1] [Table 5-2]

[0398] C max was approximately 4 hours after the first and final dose, PK parameters were similar to the Phase 1a study, and levels reached a plateau after the first dose (see FIG. 7).

[0399] (Example 9) Experiments to test whether ACU-4935 reduces VEGF upregulation caused by hypoxic conditions Figure 8 shows the protocol used to test whether ACU-4935 reduces VEGF upregulation caused by hypoxic conditions. Briefly, animals were dark-adapted for 16 hours and then administered ACU-4935. Two hours after administration, animals were photobleached at 50,000 lux for 10 minutes and then allowed to recover in the dark for 2 hours. Hypoxia was induced with 6% O2 for 6 hours. Some animals were euthanized and samples were collected at time 0. Another portion of animals were returned to the dark for 2 hours before being euthanized and samples were collected.

[0400] Samples were examined for VEGF protein expression (FIG. 9) and VEGF mRNA expression (FIG. 10). After treatment with ACU-4935, minor differences in VEGF protein expression were observed. VEGF mRNA levels were decreased at time 0 and increased slightly after treatment with ACU-4935, compared to vehicle controls, 2 hours after hypoxia.

[0401] (Example 10) Intraocular distribution of [14C]-ACU-4429 in beagle dogs ACU-4429(C 16 H 25 NO2·HCl) is an oral visual cycle regulator that has been shown to reduce rod visual system activity, thereby reducing metabolic load on the retina.

[0402] 0.3mg / kg 14 The following experiment was performed in male beagle dogs to investigate the pharmacokinetic profile, intraocular distribution, and excretion of ACU-4429 and its metabolites after single and repeated oral administration of [C]-ACU-4429 (40 μCi / kg).

[0403] As a powder in a capsule 14 A total of 36 non-fasted male beagle dogs were administered [C]-ACU-4429 (0.3 mg / kg, 40 μCi / kg) as a single oral dose or multiple doses (once daily for 7 days). Mass balance was assessed through 168 hours after the single dose or through 336 hours after the first daily dose; urine and feces were analyzed for radioactivity and metabolic profiling. Blood was collected at 0.25, 1, 2, 4, 8, 12, 48, 72, 96, 168, and 192 hours after the final dose; blood and plasma were analyzed for radioactivity and metabolic profiling. Ocular tissues (choroid, iris ciliary body, and RPE) were collected at 4, 8, 12, 24, 48, 72, and 168 hours (3 animals / time point) after the final dose and analyzed for radioactivity (right eye) or metabolic profiling (left eye).

[0404] In beagle dogs, 14 C]-ACU-4429 was rapidly absorbed (T max= 4 hours) and was cleared from plasma, with the majority of the radioactivity not being selectively associated with RBCs. Radioactivity was rapidly cleared through urine and feces (46% and 44%, respectively), and clearance from plasma was essentially complete 48 hours after dosing. Other data showed that the parent molecule of ACU-4429, despite rapid systemic clearance, selectively distributes to melanin-containing ocular tissues, including the presumed site of VCM action, the RPE (see Figures 11 and 12). In ocular tissues, ACU-4429-C max was 278-fold higher than that in plasma after 7 consecutive days of oral dosing (930 vs. 3.34 ng-eq / g) (Figure 11). References

[0405] 1 Kubota et al., Retina, 2012, 32(1): 183-188.

[0406] 2 Sparrow et al., Vision Res., 2003, 43(28): 2983-2990; Travis et al., Ann. Rev. Pharmacol. Toxicol., 2007: 47: 469-512.

[0407] (Example 11) VCM as an inhibitor of retinal neovascularization Under dark conditions, retinal ion channels open, allowing excess ions to flow into retinal cells. The retina requires energy and oxygen to flush out the excess ions. Under normal health conditions, the blood supply to the retina is barely sufficient to support this process, which generates more heat and consumes more oxygen than any other cellular function. When the blood supply is compromised, as often happens in diabetic patients, hypoxia can develop in the retina. To compensate, the retina produces new, small, leaky blood vessels, resulting in proliferative diabetic retinopathy.

[0408] Visual cycle modulators (VCMs), such as ACU-4420 and ACU-4935, inhibit the isomerases of the visual cycle. 2 , thereby mimicking a condition constitutive of light signaling and reducing dark current (see FIG. 14). Without being bound by theory, it is believed that reducing dark current should reduce the metabolic burden and associated oxygen demand in the retina, reducing hypoxia and reducing production of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF), resulting in inhibition of new blood vessel growth.

[0409] This study determined the effects of the VCMs ACU-4429 and ACU-4935 on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). 3-5

[0410] 129 SvE mouse pups (PO) were treated as diagrammed in Figure 15. ACU-4429 (0.03-10 mg / kg), ACU-4935 (0.3 mg / kg / day), positive control (ruboxistaurin at 10 mg / kg / day), or vehicle were administered intraperitoneally twice for 4 days. Parameters for ACU-4429 and ACU-49359 [Table 6]

[0411] Pups were euthanized on P17, when neovascularization was maximal, and eyes were enucleated for analysis. If retinoids were to be extracted, mice were transferred to a dark room on P16 and euthanized under red light.

[0412] Areas of retinal neovascularization were visualized by isolectin staining of flat-mount preparations and quantified with the lasso tool in Adobe Photoshop; total area of ​​neovascularization represented the sum of individual areas across the retina, and percentage of neovascularization was relative to the total retinal area. 4Retinoids were extracted from the right eye under red light and analyzed for 11-cis-ROL-oxime content, which indicates the concentration of 11-cis-ROL and as an index of cyclic isomerase activity.

[0413] Statistical analysis was performed using GraphPad Prism software.

[0414] In mice with OIR, treatment with ACU-4420 or ACU-4935 reduced the area of ​​retinal neovascularization compared to treatment with vehicle. The area of ​​retinal neovascularization was reduced by 32% with ACU-4429 (3 mg / kg / day), 23% with ACU-4935 (0.3 mg / kg / day), and 29% with ruboxistaurin (10 mg / kg / day, positive control); the mean reduction was significantly (p<0.05) higher than vehicle for both VCMs and not significantly (p<0.05) different from ruboxistaurin.

[0415] ACU-4429 dose-dependently inhibits angiogenesis and the production of 11-cis-RAL with ED50 values ​​of 0.46 mg / kg and 0.88 mg / kg, respectively. References

[0416] 1. Arden et al., Br. J. Opthalmol., 2005; 89(6): 764-769.

[0417] 2. Kubota et al., Retina, 2012; 32(1): 183-188.

[0418] 3. Chan et al., Lab. Invest., 2005; 85(6): 721-733.

[0419] 4. Connor et al., Nat. Protoc., 2009; 4(100: 1565-1573.

[0420] 5. Yoshida et al., FASEB J., 2010; 24(6): 1759-1767.

[0421] (Example 12) Electroretinogram materials and methods Light flash calibration ERG stimulation was performed using an Espion e-stimulator equipped with a ColorDome Ganzfeld stimulator. 2 (Diagnosys LLC, Lowell, MA). The rate of photoisomerization per rod for a green LED flash (R * The light flux (f) is calculated by measuring the flux density incident on an integrating radiometer (IL1700; International Light, Newburyport, Mass.) placed at the rat's cornea and following the procedure detailed by Lyubarsky and Pugh (1996). The LED is treated as monochromatic, equal to 530 nm. The flash intensity is

number

number

[0422] Calibration of bleaching light Bleaching is produced using an Ektagraphic IIIB slide projector (Eastman Kodak, Rochester, NY) equipped with an EXR (300 W) halogen lamp (color temperature 3350°). A ping-pong ball cut vertically in half is attached to the eye to diffuse the light. The projector is placed on a stand so that the lens is approximately 6 cm from the surface of the ping-pong ball. The power of the light is measured using an integrating feature-stopping radiometer placed under the ping-pong ball at the level of the rat's head. The number of photons (quanta cm) incident on the photodetector is measured. -2 s -1 The calculation of fading intensity is done using equation (2) and assuming λ = 500 nm.

number

[0423] preparation Dark-adapted subjects were administered a loading dose of approximately 75 mg kg -1 of ketamine, and 8 mg kg -1 The animals are anesthetized with 100 mg of xylazine. An additional dose (50% of the loading dose) is then injected intramuscularly. The pupils are dilated with a combination of 1% phenylephrine hydrochloride and 0.2% cyclopentolate hydrochloride (Cyclomydril; Alcon, Fort Worth, TX). The cornea is anesthetized with one drop of 0.5% proparacaine hydrochloride. A Burian-Allen bipolar electrode (Hansen Laboratories, Coralville, IA) is placed on the cornea and an external electrode is placed on the tail. The red light is turned off and the animals are left in complete darkness for an additional 10 minutes to allow for full dark adaptation before the experiment begins.

[0424] Activation of light signaling On the first testing day, animals are assigned at half risk so that half of the pups from each litter (rounded up if the number is odd) participate in studies of light signaling activation and inactivation and post-receptor retinal function, and the remainder participate in the bleaching experiment. Rod light response properties are estimated from the ERG by fitting parameters of Hood and Birch's (1992) formulation of the Lamb and Pugh (1992; Pugh and Lamb, 1993) model of the biochemical process involving activation of light signaling to the a-wave elicited by the five brightest flashes:

number

[0425] In this model, i is the flash intensity (R * ), where t is the elapsed time (s). The values ​​of the free parameters of this model, i.e., Rm P3 , S, and t d is optimized using the conventional procedure for minimizing the sum of squared deviations (fmins; MATLAB R11, The Math-works, Natick, MA). Rm P3 is the amplitude (μV) of the saturated rod response, which is proportional to the magnitude of the dark current and depends on the number of channels available for light closure in the ROS (Lamb and Pugh, 1992; Pugh and Lamb, 1993), which, under normal conditions, depends directly on the length of the ROS (Reiser et al., 1996). S is the sensitivity (R *-1 s -2 ) parameter, and the amplitude constant A summarizes the kinetics of the series of processes that are initiated by the photoisomerization of rhodopsin and lead to the closure of the channel in the plasma membrane of the photoreceptor. d is a fractional lag (s). The fitting of the model is restricted to the leading edge of the a wave.

[0426] Inactivation of light signaling In the same rats, using the double-flash paradigm, approximately 150R * The time course of the rod response to a conditioning flash (CF) of "green" (λmax approximately equal to 530 nm) that results in a saturation of the rods is obtained. This green flash elicits the a-wave of the response of less than half the saturated rods, but is nevertheless sufficient to completely suppress the dark current. First, only the response to CF is recorded. Then, the rods are saturated (approximately 10,000 R * ) Determine the amplitude of the response to an intense "white" xenon arc probe flash. The amplitude of the PF response, i.e., a, is measured 8 ms after presentation (just before the trough of the a-wave). maxThe CF and PF are then presented together, divided into 10 predetermined stimulus time intervals (10 ms, 20 ms, 50 ms, 0.1 s, 0.15 s, 0.2 s, 0.4 s, 0.7 s, 1 s, and 1.4 s). In the double flash condition, the response to the CF recorded alone was measured for each stimulus time interval t, a sat,t This served as a baseline for measuring the amplitude of the response to PF at t. Thus, t The ratio of the dark current suppressed by CF is

number

[0427] To obtain the time course of inactivation, the trough of the rod response is determined and a line is fitted through the recovery phase. The latency (ms) to 50% recovery is found.

[0428] Post-receptor functions In the same animals, rod-mediated post-receptor function is assessed from the b-wave of the ERG. * A series of 13 "green" flashes, delivered from the MRI scanner, were used to elicit b-wave responses. The amplitude of such responses (μV) was plotted against the parameters of the Naka-Rushton function

number

[0429] Recovery from fading In a second set of experiments performed in the cohort, we evaluate the recovery of dark current from bleaching. A PF (10,000R) that saturates rods is administered to dark-adapted eyes. * ) is used to determine the magnitude of the dark current. After bleaching exposure, the response to PF is monitored at 2 min intervals for approximately 40 min. At each time point, the fraction of dark adaptation recovered (1-SFt) is calculated. The time at which the light response of saturated rods recovers by 50%, i.e., t 50 is found by optimizing the parameters of the function,

number

[0430] stimulus delivery The timing and intensity of ERG stimulation is computer controlled. The stimulus time intervals and the number of sweeps, averaged over a range of intensities, used to assess the sensitivity and amplitude of receptor and post-receptor responses are detailed below. For inactivation experiments, responses to conditioning flashes averaged 8, responses to probe flashes averaged 4, and in the double-flash condition, all traces were recorded 1 min apart, averaging 2 sweeps. In bleaching experiments, the probe flash was delivered once every 2 min. [Table 7]

[0431] Analysis of retinal vessels The tortuosity of the vessels is determined in both eyes of the subjects using non-invasive techniques, which is necessary in longitudinal studies. The OIR model used in this study is characterized by a 100% NV rate; it is also characterized by tortuous retinal vessels. In patients, the posterior pole is the area of ​​greatest importance for diagnosing high-risk ROP. Correspondingly, after each ERG session, a wide-area image of the fundus showing the major vessels of the retina is obtained and the images are composited to show a complete view of the posterior pole (defined here as the area within a circle wrapped around the vortex vein and concentric with the optic disc, which defines the equator). Arterioles are identified and their tortuosity is measured using RISA software, as described above (Akula et al., 2007; Akula et al., 2008; Gelman et al., 2005; Hansen et al., 2008; Martinez-Perez et al., 2002, 2007). Briefly, each vessel is cropped from the main image and segmented individually. If necessary, the segmented images are manually edited to remove extraneous features, e.g., background choroid vasculature. RISA creates a skeleton and marks end and branching points. The user then selects vessel segments for analysis, and RISA automatically calculates the integral curvature (IC) for each selected vessel segment. IC captures any departure from a straight course and is the sum of the angles along the vessel, normalized by the vessel length (radians pixels -1 ). Thus, theoretically, a straight vessel has IC=0. A high IC captures enough vessels that a physician would call tortuous. Arteriolar tortuosity (TA (radians pixel -1 ) is calculated for each subject as the average integrated tortuosity of all measurable arterioles in both eyes (median 10).

[0432] (Example 13) Human clinical trials for retinopathy of prematurity OBJECTIVES:The primary objective of this study is to determine the safety of the clinical trial candidate when administered orally to newborns with ROP. An additional objective of this study is to determine the efficacy of the clinical trial candidate in reducing the progression of ROP through serial ophthalmic examinations scheduled at different intervals depending on the severity of ROP, compared to that observed in a control group receiving conventional care (treatment recognized by the ETROP Cooperative Group).

[0433] METHODS: An interventional, randomized, controlled pilot study will be conducted to determine the safety and efficacy of a clinical trial candidate when used in addition to conventional methods (treatments accepted by the ETROP Cooperative Group) versus conventional methods alone to treat preterm infants (<32 weeks gestational age) with stage 2 ROP (zone II-III without plus).

[0434] Patients were required to meet the following exclusion criteria at study enrollment: (1) premature birth with bradycardia >10 times per day (HR <90 bpm); (2) atrioventricular (aV) block (2nd or 3rd degree); (3) significant congenital heart anomalies (not including patent ductus arteriosus, patent foramen ovale, or small ventricular septal defect); (4) heart failure; (5) hypotension (mean blood pressure <45 mmHg); (6) hypoglycemia (<50 mg / dL); and (7) platelet count <100,000 / mm 3 If any of the following is satisfied, it will be excluded.

[0435] To compare the proportion of newborns progressing to more severe ROP in the treatment and control groups, the estimated sample size was calculated considering a normal distribution, an alpha error of 0.05, and a power of 80%. The sample size for each group is 22. The incidence of progression from stage 2 ROP to higher stages increases with decreasing gestational age. To ensure an even distribution of gestational age in both groups (treatment and control), the recruited newborns will be randomized and classified according to gestational age into three different groups: group 1 (23-25 ​​weeks), group 2 (26-28 weeks), and group 3 (29-32 weeks).

[0436] At the beginning of the study, patients in each gestational age group will be further divided into two groups, one of which will receive the clinical development candidate in suspension form orally at a dose of 0.5 mg / kg / 6 hours, and the other will receive a placebo suspension. Both the treatment and placebo groups will continue their conventional treatment as approved by the ETROP Cooperative Group. Both the treatment and placebo groups will undergo an ophthalmological examination at 40 weeks of gestation. Ophthalmologists will not know which patients will receive the clinical development candidate or the placebo.

[0437] Evaluation: Cardiac and respiratory parameters (heart rate, blood pressure, oxygen saturation, respiratory support) are continuously monitored to determine the safety of the clinical candidate. Immediately after diagnosis of stage 2 ROP, blood samples are taken to check kidney, liver, and metabolic balance. The Kruskal-Wallis test is used to evaluate possible differences between neonates receiving the clinical candidate and those receiving a placebo. Safety is also determined by relative risk (RR). RR is calculated as the ratio between the likelihood of side effects in the treatment group and that likelihood in the control group. RR is also calculated as the ratio between the likelihood of ROP progressing to more severe ROP in the treatment group and that likelihood in the control group. In this case, RR values ​​lower than 1 are associated with the efficacy of the treatment. RR is obtained for each gestational age group, if necessary.

[0438] For efficacy, all neonates (treatment and control) are evaluated at 40 weeks of gestation using a recently published battery of behavioral tests designed to assess various aspects of visual function (Ricci et al., Early Hum Dev. 2008 Feb;84(2):107-13). The behavioral tests include items that assess eye movements (spontaneous and in response to targets), the ability to fixate and follow black / white targets (horizontal, vertical, and arc), responses to colored targets, the ability to distinguish between black and white stripes of increasing spatial frequency, and the ability to maintain attention on a target moving slowly away from the infant. Visual function is assessed at 1, 4 1 / 2, 12, 18 and 24 months corrected age in terms of visual acuity (binocular and monocular) measured by well-known instruments based on forced choice preference (Teller acuity cards), stereopsis, and visual motricity (Ricci et al. J Pediatr. 2010 Apr;156(4):550-5).

[0439] (Example 14) Human clinical trials for choroidal neovascularization OBJECTIVES:The primary objective of this study is to determine the safety of the clinical development candidate when administered orally to patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). An additional objective of this study is to determine the efficacy of the clinical development candidate for the treatment of choroidal neovascularization secondary to age-related macular degeneration (AMD) compared to that observed in a placebo-treated control group.

[0440] Methods: An interventional randomized controlled pilot study will be conducted to compare the safety and efficacy of the clinical development candidate versus placebo in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Patients will be eligible if they are (1) male or female aged 50 years or older; (2) diagnosed with primary or recurrent subfoveal CNV secondary to AMD, including those with predominantly classic, minimally classic, or active occult lesions without classic components; (3) have a BCVA score of 73 to 24 letters (approximately 20 / 40 to 20 / 320 Snellen equivalent visual acuity) in the study eye, inclusive; (4) the total CNV area (including both classic and occult components) is at least 50% of the total lesion area, and (5) the lesion area is 12 disc area or less.

[0441] Patients were classified as having the following conditions: (1) Snellen equivalent visual acuity of 20 / 200 or worse in the fellow eye; (2) presence of angioid streaks, presumed ocular angioplasmosis, myopia (greater than -8 diopters), or CNV secondary to causes other than AMD in the study eye; (3) subfoveal fibrosis or atrophy in the study eye; (4) history of vitreous hemorrhage, retinal break, or rhegmatogenous retinal detachment or macular hole (stage 3 or 4) in the study eye; (5) active ophthalmia or ocular infection or a history thereof in the study eye within 30 days prior to screening; (6) uncontrolled glaucoma in the study eye; (7) treatment with verteporfin, external beam radiation therapy, subfoveal focal laser photocoagulation, vitrectomy, submacular hemorrhage surgery, or transpupillary thermotherapy in the study eye within 30 days of screening; (8) history of vitreous hemorrhage, retinal break, or macular hole (stage 3 or 4) in the study eye within 30 days prior to screening in the study eye; (9) Previous treatment for neovascular AMD with antiangiogenic agents (e.g., pegaptanib, ranibizumab, bevacizumab, anecortave acetate, corticosteroids, protein kinase C inhibitors, squalamine, siRNA, VEGF-Trap) in the study eye; (10) History of intraocular surgery in the study eye, including pars plana vitrectomy, but excluding minor cataract surgery, >60 days prior to screening; or (11) History of YAG laser post-cataract surgery in the study eye within 30 days prior to screening.

[0442] At the beginning of the study, patients will be divided into six groups. The clinical trial candidate will be administered orally in tablet form at doses of 2 mg / day, 5 mg / day, 7 mg / day, 10 mg / day, and 20 mg / day, respectively, to patients in the first five groups for three months. A placebo will be administered orally in tablet form to patients in the sixth group for the same period. Both treatment and placebo groups will undergo eye examinations at the end of each month. Ophthalmologists will not know which patients will receive the clinical trial candidate or the placebo.

[0443] Evaluation: To determine the safety of the clinical candidate, cardiac and respiratory parameters (heart rate, blood pressure, oxygen saturation, respiratory support) are monitored after oral administration of the clinical candidate. Blood samples are taken to check the kidney, liver, and metabolic balance. The safety of the clinical candidate is also determined by the relative risk (RR). The RR is calculated as the ratio between the probability of side effects in the treatment group and that probability in the control group. The RR is also calculated as the ratio between the probability of DR progressing to more severe DR in the treatment group and that probability in the control group. In this case, a RR value lower than 1 is associated with the effectiveness of the treatment.

[0444] To determine efficacy of the clinical development candidates, outcome measures include incidence of ocular and non-ocular adverse events, percentage of patients with an improvement in visual acuity (VA) of 15 or more letters from baseline at 3 months, percentage of patients with a loss in VA of 15 or more letters from baseline at 3 months, and mean change in VA and mean change in central retinal thickness (CRT) at 3 months from baseline.

[0445] (Example 15) Human clinical trials for retinal neovascularization associated with uveitis The primary objective of this study is to determine the safety of the clinical development candidate when administered orally to patients with RNV associated with uveitis. An additional objective of this study is to determine the efficacy of the clinical development candidate for the treatment of RNV associated with uveitis compared to that observed in a placebo-treated control group.

[0446] An interventional randomized controlled pilot study will be conducted to compare the safety and efficacy of the clinical development candidate versus placebo in patients with retinal neovascularization (RNV) associated with uveitis. Patients are eligible if they are (1) men and women aged 18-70 years who have non-infectious intermediate or posterior uveitis or panuveitis in at least one eye and are otherwise healthy, (2) have macular edema with mean central retinal thickness ≥ 250 μm; (3) have a vitreous haze score ≥ 1 but ≤ 3 (based on the National Eye Institute grading system); (4) best corrected visual acuity not worse than 20 / 400 and not better than 20 / 40; and (5) have a daily prednisone dose < 1 mg / kg.

[0447] Patients were ineligible if they met one of the following conditions: (1) patients with choroidal neovascularization; (2) patients with creeping choroidopathy, acute multifocal macular pigment epitheliopathy, or white dot retino-choroidopathies (e.g., multiple vanishing white dot syndrome (MEWDS), or multifocal choroiditis); (3) macular edema associated with other ocular diseases (e.g., diabetic retinopathy); (4) patients who had previously undergone vitrectomy; (5) any ocular condition that may affect visual acuity and retinal thickness determination; (6) concurrent use of certain immunosuppressants (specific washout periods for different medications are specified in the protocol); (7) recent or within the last 6 months use of systemic medications known to be toxic to the lens, retina, or optic nerve (e.g., deferoxamine, chloroquine, and ethambutol); and (8) other protocol-specified inclusion / exclusion criteria are applicable.

[0448] At the beginning of the study, patients will be divided into six groups. The clinical trial candidate will be administered orally in tablet form at doses of 2 mg / day, 5 mg / day, 7 mg / day, 10 mg / day, and 20 mg / day, respectively, to patients in the first five groups for three months. A placebo will be administered orally in tablet form to patients in the sixth group for the same period. Both treatment and placebo groups will undergo eye examinations at the end of each month. Ophthalmologists will not know which patients will receive the clinical trial candidate or the placebo.

[0449] Evaluation: To determine the safety of the clinical candidate, cardiac and respiratory parameters (heart rate, blood pressure, oxygen saturation, respiratory support) are monitored after oral administration of the clinical candidate. Blood samples are also taken to check the renal, hepatic and metabolic balance. The safety of the clinical candidate is further determined by the relative risk (RR). The RR is calculated as the ratio between the probability of side effects in the treatment group and that probability in the control group. The RR is also calculated as the ratio between the probability of DR progressing to more severe DR in the treatment group and that probability in the control group. In this case, a RR value lower than 1 is associated with the efficacy of the treatment.

[0450] To determine efficacy of the clinical development candidate, best corrected visual acuity (BCVA) and central retinal thickness (CRT) will be assessed by qualified examiners during scheduled monthly ophthalmic examinations. Outcome measures include incidence of ocular and non-ocular adverse events, percentage of patients with an improvement in visual acuity (VA) of 15 or more letters from baseline at 3 months, percentage of patients with a loss in VA of 15 or more letters from baseline at 3 months, and mean change in VA and mean change in central retinal thickness (CRT) at 3 months from baseline.

[0451] While certain embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many modifications, changes, and substitutions can be made without departing from the scope of the present embodiments. It should be understood that various alternatives to the embodiments described herein can be used. The scope of the following claims defines the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method of treating a diabetes-related eye disease or disorder in a patient, comprising administering to the patient a compound of formula (A) or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, X is -C(R ９ ) = C(R ９ )-, -C≡C-, -C(R ９ ) ２ -O-, -C(R ９ ) ２ -C(R ９ ) ２ -, -C(R ９ ) ２ -S-, -C(R ９ ) ２ -S (O) ２ -, or -C(R ９ ) ２ -NR ９ - selected from Y is, a) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclyl, optionally substituted with alkoxy; b) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclylalkyl, optionally substituted with alkoxy; c) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted aralkyl, optionally substituted with alkoxy; or d) halogen, —OH or C １ ~C ４ Substituted or unsubstituted C, optionally substituted with alkoxy ３ ~C １０ Alkyl is selected from R １ is hydrogen, and R ２ is hydroxyl, or R １ and R ２ forms an oxo, R ７ is hydrogen, R ８ is hydrogen or CH ３ and R ９ Each independently represents hydrogen or a substituted or unsubstituted C １ ~C ４ is alkyl, R ３３ Each independently represents a halogen or a substituted or unsubstituted C １ ~C ４ alkyl, and n is 0, 1, 2, 3, or 4. The method comprises administering to the patient a therapeutically effective amount of a composition comprising:

2. 1. A method of treating an ocular disease or disorder associated with ocular neovascularization in a patient, comprising administering to a patient a compound of formula (A) or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof: 【Chemistry 2】 [In the formula, X is -C(R ９ ) = C(R ９ )-, -C≡C-, -C(R ９ ) ２ -O-, -C(R ９ ) ２ -C(R ９ ) ２ -, -C(R ９ ) ２ -S-, -C(R ９ ) ２ -S (O) ２ -, or -C(R ９ ) ２ -NR ９ - selected from Y is, a) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclyl, optionally substituted with alkoxy; b) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclylalkyl, optionally substituted with alkoxy; c) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted aralkyl, optionally substituted with alkoxy; or d) halogen, —OH or C １ ~C ４ Substituted or unsubstituted C, optionally substituted with alkoxy ３ ~C １０ Alkyl is selected from R １ is hydrogen, and R ２ is hydroxyl, or R １ and R ２ forms an oxo, R ７ is hydrogen, R ８ is hydrogen or CH ３ and R ９ Each independently represents hydrogen or a substituted or unsubstituted C １ ~C ４ is alkyl, R ３３ Each independently represents a halogen or a substituted or unsubstituted C １ ~C ４ alkyl, and n is 0, 1, 2, 3, or 4. The method comprises administering to the patient a therapeutically effective amount of a composition comprising:

3. 1. A method for treating or preventing retinopathy of prematurity, comprising administering to a patient a compound of formula (A) or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof: 【Chemistry 3】 [In the formula, X is -C(R ９ ) = C(R ９ )-, -C≡C-, -C(R ９ ) ２ -O-, -C(R ９ ) ２ -C(R ９ ) ２ -, -C(R ９ ) ２ -S-, -C(R ９ ) ２ -S (O) ２ -, or -C(R ９ ) ２ -NR ９ - selected from Y is, a) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclyl, optionally substituted with alkoxy; b) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted carbocyclylalkyl, optionally substituted with alkoxy; c) C １ ~C ４ Alkyl, halogen, —OH or C １ ~C ４ substituted or unsubstituted aralkyl, optionally substituted with alkoxy; or d) halogen, —OH or C １ ~C ４ Substituted or unsubstituted C, optionally substituted with alkoxy ３ ~C １０ Alkyl is selected from R １ is hydrogen, and R ２ is hydroxyl, or R １ and R ２ forms an oxo, R ７ is hydrogen, R ８ is hydrogen or CH ３ and R ９ Each independently represents hydrogen or a substituted or unsubstituted C １ ~C ４ is alkyl, R ３３ Each independently represents a halogen or a substituted or unsubstituted C １ ~C ４ alkyl, and n is 0, 1, 2, 3, or 4. The method comprises administering to the patient a therapeutically effective amount of a composition comprising:

4. 4. The method of claim 1, wherein n is 0, 1, or 2.

5. X is -C(R ９ ) = C(R ９ 5. The method of claim 4, wherein

6. The method of claim 4, wherein X is -C≡C-.

7. X is -C(R ９ ) ２ The method according to claim 4, wherein said alkyl group is -O-.

8. X is -C(R ９ ) ２ -C(R ９ ) ２ The method according to claim 4, wherein

9. X is -C(R ９ ) ２ The method according to claim 4, wherein -S-.

10. X is -C(R ９ ) ２ -S (O) ２ The method according to claim 4, wherein

11. X is -C(R ９ ) ２ -NR ９ The method according to claim 4, wherein

12. Y is a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted C ３ ~C １０ 12. The method of claim 5, 7, 8, 9, 10, or 11, wherein the alkyl group is alkyl.

13. 13. The method of claim 12, wherein Y is a substituted or unsubstituted carbocyclyl.

14. Y is substituted or unsubstituted C ３ ~C １０ The method of claim 12, wherein the alkyl group is an alkyl group.

15. 14. The method of claim 13, wherein the substituted or unsubstituted carbocyclyl is a substituted or unsubstituted 4-, 5-, 6- or 7-membered ring.

16. Substituted or unsubstituted C ３ ~C １０ Alkyl is substituted or unsubstituted C ３ ~C ６ The method of claim 14, wherein the alkyl group is an alkyl group.

17. Substitution C ３ ~C ６ Alkyl is C １ ~C ２ The method of claim 16 , wherein the aryl group is substituted with an alkoxy group.

18. Substitution C ３ ~C ６ Alkyl is -CH ２ CH ２ CH ２ OCH ３ 17. The method of claim 16, wherein:

19. 16. The method of claim 15, wherein the substituted or unsubstituted carbocyclyl is a six-membered ring.

20. 20. The method of claim 19, wherein the substituted or unsubstituted 6-membered ring is a substituted or unsubstituted cyclohexyl.

21. X is -C(R ９ ) ２ The method of claim 20, wherein the alkyl group is -O-.

22. R １ is hydrogen, R ２ The method of any one of claims 1 to 3, wherein is hydroxyl.

23. R １ and R ２ The method according to any one of claims 1 to 3, wherein forms an oxo.

24. R ８ The method according to any one of claims 1 to 3, wherein is hydrogen.

25. R ８ The method according to any one of claims 1 to 3, wherein is methyl.

26. X is -C(R ９ ) ２ 26. The method of any one of claims 22 to 25, wherein -O-.

27. 1. A method of treating a diabetes-related eye disease or disorder in a patient, comprising: 【Chemistry 4-1】 【Chemistry 4-2】 or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof.

28. 1. A method of treating an ocular disease or disorder associated with ocular neovascularization in a patient, comprising: 【Chemistry 5-1】 【Chemistry 5-2】 or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof.

29. A method for treating or preventing retinopathy of prematurity, comprising: 【Chemistry 6-1】 【Chemistry 6-2】 or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharma- ceutically acceptable salt thereof.

30. The composition comprises: 【Chemistry 7】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

31. The composition comprises: 【Chemistry 8】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

32. The composition comprises: 【Chemistry 9】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

33. The composition comprises: 【Chemistry 10】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

34. The composition comprises: 【Chemistry 11】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

35. The composition comprises: 【Chemistry 12】 30. The method of any one of claims 27 to 29, comprising a compound selected from:

36. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 13】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

37. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 14】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

38. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 15】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

39. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 16】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

40. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 17】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

41. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 18】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

42. 13. The composition according to claim 12, wherein the composition has the structure: 【Chemistry 19】 or a stereoisomer, N-oxide or pharma- ceutically acceptable salt thereof.

43. 43. The method of any one of claims 1 to 42, wherein the composition is administered orally to the patient.

44. 44. The method of any one of claims 1 to 43, wherein the composition is administered once daily.

45. 45. The method of any one of claims 1 to 44, wherein treatment improves the patient's central vision.

46. 46. ​​The method of any one of claims 1 to 45, further comprising administering one or more additional therapeutic regimens.

47. 47. The method of claim 46, wherein the one or more treatment regimens are laser treatment, cryotherapy, fluorescein angiography, vitrectomy, corticosteroids, anti-vascular endothelial growth factor (VEGF) treatment, vitrectomy for persistent diffuse diabetic macular edema, pharmacological vitreolysis in the management of diabetic retinopathy, fibrates, renin-angiotensin system (ras) blockers, peroxisome proliferator-activated receptor gamma agonists, anti-protein kinase C (PKC), islet cell transplantation, therapeutic oligonucleotides, growth hormone and insulin growth factor (IGF), control of systemic factors, or combinations thereof.

48. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is diabetic retinopathy.

49. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is non-proliferative diabetic retinopathy.

50. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is proliferative diabetic retinopathy.

51. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is diabetic maculopathy.

52. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is diabetic macular edema.

53. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is neovascular glaucoma.

54. 2. The method of claim 1, wherein the diabetes-related eye disease or disorder is macular ischemia.

55. 48. The method of claim 47, wherein the one or more therapeutic regimens comprises administration of ranibizumab, bevacizumab, or pegaptanib.

56. 3. The method of claim 2, wherein the angiogenesis-associated eye disease or disorder is wet age-related macular degeneration.

57. The method of claim 2 , wherein the ocular disease or disorder associated with angiogenesis is choroidal neovascularization.

58. 3. The method of claim 2, wherein the angiogenesis-associated eye disease or disorder is selected from defects in Bruch's membrane, increased amounts of ocular vascular endothelial growth factor (VEGF), myopia, myopic degeneration, deterioration of central vision, metamorphopsia, color vision disorders, vascular hemorrhage, or a combination thereof.

59. The method of claim 2 , wherein the angiogenesis-associated ocular disease or disorder is retinal neovascularization.

60. The method of claim 3, wherein the patient is a premature infant.

61. 4. The method of claim 3, wherein the patient is further treated with supplemental oxygen.

62. A method of protecting the eye during a medical procedure requiring exposure of the eye to bright light, laser light that results in prolonged and / or excessive pupil dilation or otherwise renders the eye sensitive to light, comprising administering to a patient in need thereof a composition comprising a compound as described herein.

63. 63. The method of claim 62, wherein the composition is administered orally prior to the medical procedure.

64. 63. The method of claim 62, wherein the composition is orally administered within 24 hours prior to and / or 48 hours after the medical procedure.

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