Methods and Compositions Including Peptide Mimetics for Treating, Preventing, Inhibiting, Ameliorating, or Delaying the Onset of Ocular Conditions - Patent application

Abstract

The present disclosure generally relates to compounds (i.e., peptidomimetics), compositions (e.g., formulations or medicaments), methods, and related uses for treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject, such as a human. In some embodiments, the ocular disease, disorder, or condition may be associated with a deterioration in the health of one or more ocular ellipsoid zones of the mammalian subject. The methods and uses include administering an effective amount of a peptidomimetic (alone, formulated, and / or in combination with at least one additional therapeutic agent) to a mammalian subject in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 257,738, filed October 20, 2021, U.S. Provisional Application No. 63 / 331,412, filed April 15, 2022, and International Patent Application No. PCT / US2022 / 045908, filed October 6, 2022, each of which is incorporated by reference herein for all purposes.

[0002] The present technology relates generally to compounds (i.e., peptidomimetics), compositions (e.g., medicaments), and methods for treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject. In some embodiments, the ocular disease, disorder, or condition is associated with a deterioration in the integrity of the ellipsoid zone of one or more eyes of the mammalian subject. For example, the technology may relate to administering one or more mitochondrial targeted peptidomimetics (alone, in a formulation, and / or in combination with other active pharmaceutical ingredients) in an amount effective to treat, prevent, inhibit, ameliorate, or delay the onset of an ocular disease, disorder, or condition (e.g., macular degeneration (including (wet or dry) age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataracts, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (CPEO or simply PEO, e.g., often referred to as Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA)).

[0003] Introduction The following preface is provided to aid the reader's understanding: None of the information provided or references cited are admitted as prior art to the present technology.

[0004] Diseases, disorders, and degenerative conditions of the optic nerve and retina are the leading causes of blindness in the world. Many eye diseases, disorders, or conditions result from or are associated with mitochondrial dysfunction.

[0005] A significant degenerative condition of the retina is age-related macular degeneration (AMD). AMD is the most common cause of blindness in people over 50 years of age in the United States, and its prevalence increases with age. AMD is classified as either wet (neovascular) or dry (non-neovascular). The dry form of the disease is more common. Macular degeneration occurs when the central retina becomes distorted and thins. This change is usually age-related, but is characterized by intraocular inflammation and neovascularization (wet AMD only) and / or intraocular infection. The subsequent generation of free radicals can result in oxidative tissue damage, local inflammation, and production of growth factors (such as VEGF and FGF) and inflammatory mediators, leading to inappropriate angiogenesis in common with the wet form of AMD. Mitochondrial dysfunction is thought to play a role in age-related disorders such as AMD. (Liu et al., Appl. Sci. (2021) 11:7385). Pieramici & Ehlers report that "RPE mitochondria in AMD eyes undergo more pronounced degenerative changes, with lower mitochondrial density, organelle area, and cristae number" (Pieramici & Ehlers, presented at the 54th Annual Retina Society Meeting, September 30, 2021, slide 3).

[0006] Retinopathy is the leading cause of blindness in type I diabetes and is also common in type II diabetes. The extent of retinopathy depends on the duration of diabetes and generally begins to occur 10 years or more after the onset of diabetes. Diabetic retinopathy can be classified as non-proliferative, where retinopathy is characterized by increased microvascular permeability, edema and exudates, or proliferative, where retinopathy is characterized by neovascularization extending from the retina to the vitreous, scarring, deposition of fibrous tissue, and possible retinal detachment. Diabetic retinopathy is thought to be caused by the development of glycosylated proteins due to hyperglycemia, resulting in damage to small blood vessels in the eye. Diabetic retinopathy (often if left untreated) can progress to diabetic macular edema. Diabetic macular edema involves damage to blood vessels in the retina that progress to the point where they leak fluid into the macula, causing it to swell, which results in blurred vision. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic retinopathy. (Wu et al.Hindawi Oxidative Medicine and Cellular Longevity,Volume 2018,Article 3420187)

[0007] Glaucoma consists of a group of eye diseases that cause vision loss due to damage to the optic nerve and retinal ganglion cells (RGCs). Intraocular pressure (IOP) above 21 mmHg without optic nerve damage is known as ocular hypertension. Elevated IOP due to inadequate ocular drainage is the main cause of glaucoma. Lowering IOP reduces the risk of progressive RGC loss in glaucoma, however, no currently available treatments directly prevent RGC damage. Glaucoma often develops with ocular age or may occur as a result of ocular damage, inflammation, tumors, or in advanced cases of cataract or diabetes. It may also be caused by an increase in IOP caused by treatment with steroids. Medications that have proven effective in glaucoma reduce IOP by decreasing vitreous humor production or by promoting ocular drainage. Such agents are often vasodilators and therefore act on the sympathetic nervous system and include adrenergic antagonists. It has been stated that "...mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases..." and "...mitochondrial damage may provide a potential strategy for the treatment of glaucoma..." (Liu et al., Appl. Sci. (2021) 11: 7385).

[0008] Autosomal dominant optic atrophy (DOA) is a genetic X-linked neuro-ophthalmologic condition characterized by bilateral degeneration of the optic nerve. It affects approximately 1 in 10,000 (Denmark) to 1 in 30,000 (worldwide) individuals. Nerve damage causes vision loss. It generally begins to appear by age 10 and progresses thereafter. The disease itself primarily affects the retinal ganglion nerves. Mutations in genes known as OPA1 and OPA3, which code for mitochondrial inner membrane proteins (leading to mitochondrial dysfunction), are commonly associated with DOA.

[0009] Leber's Hereditary Optic Neuropathy (LHON) is a genetically-based inherited disease that typically begins to manifest between the ages of 15-35. In LHON, mitochondrial mutations affect the complex I subunit gene in the respiratory chain that typically results in selective degeneration of retinal ganglion cells (RGCs) and optic nerve atrophy within one year of disease onset. LHON is caused by mutations in the MT-NDI1, MT-ND4, MT-ND4L, and MT-ND6 genes, all of which are associated with the mitochondrial genome coding. LHOH affects approximately 1 in 50,000 people worldwide. It typically begins in one eye and progresses rapidly to the other eye. Subjects with LHON may eventually become legally or completely blind, often before the age of 50. LHON affects the visual acuity required for tasks such as reading, driving, and recognizing others.

[0010] Retinitis pigmentosa (RP) is a group of inherited retinal degenerative disorders characterized by progressive vision loss. RP is the leading cause of hereditary blindness in developed countries. Clinically, RP manifests as difficulty with night vision due to death of rod photoreceptors, followed by progressive loss of peripheral vision that ultimately leads to central vision impairment from secondary loss of cone photoreceptors. RP is caused by mutations in at least 87 genes. The pathogenesis of RP is not fully understood. However, mitochondrial dysfunction and oxidative damage are thought to play an important role in the pathogenesis of photoreceptor cell death in RP. (Gopalakrishnan et al.,Scientific Reports(2020)10:20382)

[0011] Pigmentary retinopathy (PR) is a frequent feature of retinitis pigmentosa. Pigmentary retinopathy is a nonspecific finding that can be found in several mitochondrial diseases, such as neurogenic anaplasia, ataxia, and retinitis pigmentosa (NARP). PR is an inherited degenerative disorder of the retina, characterized by progressive photoreceptor damage. The damage leads to photoreceptor atrophy and cell death. Patients with PR may follow an autosomal dominant, autosomal recessive, or X-linked recessive pattern. The prevalence is approximately 1 in 3-4 thousand individuals. Symptoms of the disease include night blindness (night blindness), peripheral visual field constriction, and sometimes loss of central vision or visual field.

[0012] Uveitis is a number of intraocular inflammatory diseases of the eye that often result in irreversible vision loss. Uveitis is responsible for an estimated 30,000 new cases of legal blindness each year in the United States. The disease is thought to result, at least in part, from retinal tissue damage resulting in excessive mitochondrial oxidative stress that triggers a damaging immune response.

[0013] Chronic progressive external ophthalmoplegia (CPEO) is a condition characterized primarily by loss of muscle function, including eye and eyelid movement. The condition typically presents in adults between the ages of 18-40 and slowly worsens over time. CPEO can be caused by genetic alterations in any of several genes that may be located in mitochondrial DNA or nuclear DNA. CPEO can occur as part of other underlying conditions such as ataxic neuropathy spectrum and Kearns-Sayre syndrome. These conditions may involve CPEO as well as a variety of additional features that are not shared by most individuals with CPEO.

[0014] Kearns-Sayre syndrome is a condition that affects many parts of the body, especially the eyes. The characteristics of Kearns-Sayre syndrome usually appear before the age of 20, and the condition is diagnosed by several characteristic signs and symptoms. People with Kearns-Sayre syndrome have progressive external ophthalmoplegia. Affected individuals also have an eye condition called pigmentary retinopathy, which results from the breakdown (degeneration) of the retina, giving it a spotted and striped appearance.

[0015] Leber congenital amaurosis (LCA) is a rare genetic eye disorder that affects infants. Infants are often blind at birth. LCA may be associated with mitochondrial dysfunction. (Castro-Gago et al., J. Child Neurol. (1996) 11(2):108-11) Children born with LCA have retinal light-gathering cells (rods and cones) that do not function properly. LCA is estimated to occur in 1-2 cases per 100,000 births. The disorder affects males and females in equal numbers.

[0016] Drusen are small yellow or white spots between the retinal pigment epithelium and Bruch's membrane in the retina and can be detected by an ophthalmologist during a dilated eye exam or on a retinal photograph. Drusen can also be imaged and monitored by optical coherence tomography (OCT). Drusen are composed of lipids and proteins. Drusen are the defining feature of macular degeneration. Drusen can be hard or soft. A greater number of drusen, as well as larger size drusen, indicate a higher risk of some vision loss in the future. "Hard" drusen are smaller and indicate a lower risk of vision loss than "soft" drusen. "Soft" drusen are larger clusters that come together and have less clearly defined edges. Soft drusen are more likely to lead to vision loss.

[0017] Geometric atrophy (GA) is generally considered part of the later stages of age-related macular degeneration (AMD) and refers to the progression of the disease in areas of the retina to a point where cells begin to wear out and die (i.e., atrophy).

[0018] Best corrected visual acuity (BCVA) is a measure of the best possible visual acuity that an eye can achieve using glasses or corrective lenses. It is usually measured using the Snellen lines on an eye chart. Repeated testing of BCVA over time can be used to determine whether a subject's visual acuity is steadily improving or worsening.

[0019] Low-light visual acuity (LLVA) involves standard visual acuity testing under low light conditions. This is often accomplished by adding a neutral density filter in front of the eye being tested. It is a useful visual function marker in those with geographic atrophy (GA) and neovascular age-related macular degeneration. Repeated testing of LLVA over time can be used to determine whether a subject's visual acuity is steadily improving or worsening under low light conditions.

[0020] Optical coherence tomography (OCT) is a non-invasive imaging method used to generate images of the back of the eye (i.e., the retina). OCT uses a low-powered laser to generate images of the layers of the retina and optic nerve. The cross-sectional images are three-dimensional and color-coded. OCT can measure the thickness of the retina and optic nerve. OCT can be used to diagnose and manage glaucoma, AMD, diabetes-related retinopathy, cystoid macular edema, macular pucker, and macular holes.

[0021] Spectral-domain optical coherence tomography (SDOCT) is an interferometric technique that provides depth-resolved tissue structure information encoded in the magnitude and delay of backscattered light by spectral analysis of interference fringes. SDOCT increases axial resolution by 2-3 times and scan speed by 60-110 times compared to conventional (TD)OCT.

[0022] The ellipsoid zone can be mapped using SCOCT, and the health (or changes) of the ellipsoid zone can be determined from such mapping / scanning activity. (Itoh et al., Br J Ophthalmol. (2016) 100(3):295-299). This technique can assess the structure of the external limiting membrane (ELM), ellipsoid zone (EZ), interdigitation zone (IZ), and retinal pigment epithelium (RPE). Ibid. Use of this technique can access EZ health and EZ-RPE changes. Ibid. In particular, the EZ and ELM have been associated with visual outcomes and prognosis in numerous macular conditions, such as age-related macular degeneration (AMD). Ibid. Itoh et al. suggest that the utility of SDOCT as an assessment tool for EZ health in clinical trials and disease prognosis / management may prove particularly useful.

[0023] Swept-source optical coherence tomography (SS-OCT) and optical coherence tomography angiography (OCTA) are relatively new techniques that allow for better resolution of the retinal pigment epithelium (RPE), Bruch's membrane (BM), and choriocapillaris (CC) structures. (Zhou et al. Biomedical Optics Express (2020) 11(4):1834-1850) Using this technique, it is possible to generate relative distance and thickness maps of the RPE-BM-CC complex. Ibid. The use of these techniques may provide a better understanding of the CC in three dimensions and may further explore the potential functional relationships between the RPE, BM, and CC, as well as their involvement in age-related eye diseases. Ibid.

[0024] The ellipsoid zone (EZ) of the eye is a mitochondrial-rich tissue (Ball et al., Sci. Adv. 8, eabn2070 (2022)). The ellipsoid zone can be imaged using optical coherence tomography (Fujita et al., Scientific Reports (2019) 9: 12433). The health of the EZ can be quantified (Fugita et al.). There is a clear relationship between the health of the ellipsoid zone and visual function (Fugita et al., Figure 3). Ball et al. suggest that densely packed mitochondria in the ellipsoid "focus" light for entry into the outer segment and that healthy mitochondrial structure (including cristae structures) may be important for generating the Stiles-Crawford effect (SCE) in mammals and for maintaining visual resolution in mammals. Pieramici & Ehlers report the possibility of mapping the ellipsoid zone, thereby observing the ellipsoid zone, and monitoring changes in the health of the ellipsoid zone. (Pieramici & Ehlers, presented at the 54th Annual Retina Society Meeting, September 30, 2021.) Pieramici & Ehlers further reported the use of the Sub-RPE compartment map as a means to detect and monitor drusen formation and RPE atrophy in subjects. In the reported study (reporting results from a Phase 2 clinical trial involving treatment with elamipretide), Pieramici & Ehlers concluded, inter alia: (i) "mean BCVA and LLVA in NCGA and HRD patients significantly improved at 24 weeks [of treatment with elamipretide]" and (ii) "baseline higher-order OCT parameters, such as EZ integrity, correlated with improved LLVA in elamipretide-treated eyes" (slide 15 of Pieramici & Ehlers).

[0025] In summary, there are many eye diseases for which there remains a need for treatments / therapies or improved treatments / therapies. For example, there remains a need for treatments / therapies or improved treatments / therapies to address eye diseases, disorders, or conditions such as macular degeneration (including (wet or dry) age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataracts, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA). The preceding discussion addresses these needs. Summary of the Invention

[0026] The present technology generally relates to treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammal via administration of a therapeutically effective amount of at least one peptidomimetic to a subject in need thereof. Such a peptidomimetic can be a mitochondrial-targeted peptidomimetic. For example, such a peptidomimetic can be a compound of formula I (defined below), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a compound of formula II (defined below), such as the Tris-HCl salt of formula II (identified below as formula IIa). In some embodiments, the peptidomimetic is a compound of formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, or formula V, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof.

[0027] For example, in one aspect, the disclosure provides a method of treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0028] In one aspect, the disclosure provides for the use of a composition in the preparation of a medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of (i) an ocular disease, disorder, or condition, or (ii) deterioration of ellipsoid zone integrity in one or more eyes, in a mammalian subject in need thereof, the composition comprising a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. For example, the peptidomimetic can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma-ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0029] In some embodiments, the composition is produced by dissolving or suspending the peptidomimetic in a diluent, adjuvant, excipient, or vehicle, such as water or a solvent mixture containing water. In some embodiments, the composition or medicament further comprises a preservative. In some embodiments, the preservative is present in the composition or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the composition or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the composition or medicament at a concentration of 0.5-1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the composition or medicament at a concentration of 1-2% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the composition or medicament at a concentration of 2-3% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the medicament at a concentration of 3-5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the medicament at a concentration of greater than 5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the medicament at a concentration of greater than 10% (weight / volume).

[0030] In one aspect, the disclosure provides a formulation or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of (i) an ocular disease, disorder condition, or (ii) deterioration of ellipsoid zone integrity in one or more eyes in a mammalian subject in need thereof, the formulation or medicament comprising a therapeutically effective amount of at least one peptidomimetic, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. For example, the peptidomimetic used in the formulation can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (i.e., Formula II), or a pharma-ceutically acceptable salt (e.g., (Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0031] In some embodiments, the formulation or medicament is prepared by dissolving or suspending the peptidomimetic in a diluent, adjuvant, excipient, or vehicle, such as water or a solvent mixture containing water. In some embodiments, the formulation or medicament further comprises a preservative. In some embodiments, the preservative is present in the formulation or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 0.5-1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 1-2% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 2-3% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 3-5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the formulation or medicament at a concentration of greater than 5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the formulation or medicament at a concentration of greater than 10% (weight / volume).

[0032] In one aspect, the disclosure provides a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of deterioration of ellipsoid zone health in one or more eyes of a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic. For example, the peptidomimetic can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (II), or a pharma-ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is of formula I, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R 2b is H or CH 3 and R 3 and R 4are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0033] In one aspect, the disclosure provides a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of geometric atrophy in a subject in need thereof, the subject being diagnosed with age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic. For example, the peptidomimetic can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (II), or a pharma- ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R 2b is H or CH 3 and R 3 and R4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0034] In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic is a peptidomimetic of Formula I, wherein AA 1 teeth, [ka] Selected from AA 2 teeth, [ka] Selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H and R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is [ka] In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic is a peptidomimetic of Formula I, wherein AA 1 teeth, [ka] and A.A. 2 teeth, [ka] and R 1 teeth, [ka] and R 2a teeth, [ka] and R 7 is H and X is [ka] In some embodiments of the aforementioned methods, uses, composition formulations, or medicaments, the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV, [ka] [ka] or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0035] In some embodiments of the aforementioned methods, uses, composition formulations, or medicaments, the ocular disease, disorder, or condition is selected from the group consisting of macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataracts, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA).

[0036] In some embodiments of the above-mentioned methods, uses, compositions, formulations, or medicaments, the subject is a human. In some implementations of the above-mentioned methods, the subject is diagnosed as having age-related macular degeneration (AMD). In some implementations of the above-mentioned methods, the subject has drusen. In some implementations of the above-mentioned methods, the subject is diagnosed as having geometric atrophy (GA). In some implementations of the above-mentioned methods, the subject is diagnosed as having glaucoma.

[0037] In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered orally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered subcutaneously. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered topically. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intraocularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered ocularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intranasally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered systemically. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intravenously. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intraperitoneally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intradermally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intrathecally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intracerebroventricularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered iontophoretically. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered transmucosally. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or agent is administered intravitreally.In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or medicament is administered intramuscularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or medicament is administered topically. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or medicament is administered intraocularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic composition, formulation, or medicament is administered ocularly. In some embodiments of the aforementioned methods, uses, compositions, formulations, or medicaments, the peptidomimetic, composition, formulation, or medicament is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

[0038] In some embodiments, practicing the methods disclosed herein can further include administering an additional therapeutic agent (in addition to one or more peptidomimetics). The additional therapeutic agent can be selected from the group consisting of, for example, antioxidants, metal complexers, anti-inflammatory agents, antibiotics, and antihistamines. In one embodiment, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, alpha-lipoic acid, coenzyme Q, glutathione, or a carotenoid.In one embodiment, the practice of the method includes administering to the patient an effective amount of any of the following: alpha lipoic acid, aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, chrysoeriol, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demecarium, dexamethasone ... diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, humanin, hydrocortisone, idoxuridine, indomethacin, isoflurane, ketorolac, ketotifen, latanoprost, levobetaxolol, levobunol levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, metformin, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, necrostatin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, PU-61, ranibizumab, resveratrol, rimex The method may further comprise administration of an additional therapeutic agent selected from the group consisting of solon, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, TPP-Niacin, travoprost, triamcinuron, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarubine, xylometazoline, ZLN005, pharma- ceutically acceptable salts thereof, and combinations of two or more of the foregoing.In some embodiments, the additional therapeutic agent includes carbachiol (Carbastat® or Carboptic®), polocarpine (Salagen®), timolol (Timoptic®), betaxolol (Betoptic® or Keflone®), carteolol (Cartrol® or Ocupress®), levobunolol (Liquifilm®), brimonidine (Lumify® or Mirvaso®), apraclonidine (Iopidine®), latanoprost (Xalantan®), travoprost (Travatan®), or cefotaxime (Citrolev®). In some embodiments, the medicaments may include, but are not limited to, acetazolamide (Diamox®), methazolamide (Neptazane®), brimonidine tartrate / timolol maleate (Combigan®), timolodorzolamide (Cosopt®), travoprost-timolol (DuoTrav®), and / or latanoprost and timolol maleate (Xalacom®).

[0039] In some embodiments, the composition, formulation, or medicament can further comprise an additional therapeutic agent. The additional therapeutic agent can be selected from the group consisting of, for example, antioxidants, metal complexing agents, anti-inflammatory agents, antibiotics, and antihistamines. In one embodiment, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, alpha-lipoic acid, coenzyme Q, glutathione, or a carotenoid.In one embodiment, the practice of the method includes administering to the patient an effective amount of any of the following: alpha lipoic acid, aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, chrysoeriol, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demecarium, dexamethasone ... diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, humanin, hydrocortisone, idoxuridine, indomethacin, isoflurane, ketorolac, ketotifen, latanoprost, levobetaxolol, levobunol levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, metformin, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, necrostatin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, PU-61, ranibizumab, resveratrol, rimex The method may further comprise administration of an additional therapeutic agent selected from the group consisting of solon, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, TPP-Niacin, travoprost, triamcinuron, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarubine, xylometazoline, ZLN005, pharma- ceutically acceptable salts thereof, and combinations of two or more of the foregoing.In some embodiments, the additional therapeutic agent includes carbathiol (Carbastat® or Carboptic®), polocarpine (Salagen®), timolol (Timoptic®), betaxolol (Betoptic® or Keflone®), carteolol (Cartrol® or Ocupress®), levobunolol (Liquifilm®), brimonidine (Lumify® or Mirvaso®), apraclonidine (Iopidine®), latanoprost (Xalantan®), travoprost (Travatan®), These may include, but are not limited to, bimatoprost (Lumigan®), talfluprost (Taflotan®), unoprostone isopropyl (Rescula®), dorzolamide (Trusopt®), brinzolamide (Azopt®), acetazolamide (Diamox®), methazolamide (Neptazane®), brimonidine tartrate / timolol maleate (Combigan®), timolodorzolamide (Cosopt®), travoprost-timolol (DuoTrav®), and / or latanoprost and timolol maleate (Xalacom®). [Brief description of the drawings]

[0040] [Figure 1A] 1 is a graph of data comparing the concentrations of either elamipretide or the compound of Formula IIa in rabbit plasma at various time points following subcutaneous (SC) injection. [Figure 1B] 1 is a graph of data comparing the concentrations of either elamipretide or the compound of Formula Ha in rabbit plasma at various time points following topical administration of eye drops twice daily for five days. [Figure 2A] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in rabbit retina at various time points following subcutaneous (SC) injection. [Figure 2B] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in rabbit retina at various time points following topical administration of eye drops twice daily for five days. [Diagram 3] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in rabbit conjunctiva at various time points following topical administration of eye drops twice daily for five days. [Figure 4] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in rabbit corneas at various time points following topical administration of eye drops twice daily for five days. [Diagram 5] 1 is a graph of data comparing the concentrations of either elamipretide or the compound of Formula Ha in the aqueous humor of rabbits at various time points following topical administration of eye drops twice daily for five days. [Figure 6] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in rabbit sclera at various time points following topical administration of twice daily eye drops for five days. [Figure 7] 1 is a graph of data comparing the concentration of either elamipretide or the compound of Formula IIa in the rabbit optic nerve head at various time points following topical administration of twice daily eye drops for five days. [Figure 8A] Schematic of the experimental approach using nitrite modification of the extracellular matrix (ECM) as a model of aging Bruch's membrane. RPE cells = retinal pigment epithelial cells. [Figure 8B] Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8C]Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8D] Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8E] Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8F] Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8G]Images showing differentiation of human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from donor fibroblasts. Fibroblasts (FIG. 8B) were reprogrammed into undifferentiated human iPSC colonies (FIG. 8C). iPSCs were induced to form embryoid bodies (EBs) in suspension culture (FIG. 8D). Induction of neural rosettes by day 14 post-differentiation (FIG. 8E), and a pigmented monolayer of iPSC-derived RPE cells formed by day 45 post-differentiation (FIGS. 8F and 8G). [Figure 8H] Images show that after differentiation, iPSC-derived RPE cell lines from age-related macular degeneration (AMD) donors stained positive for ZO-1, NA-K ATPase, and RPE65. Nuclei stained with DAPI. Scale bar = 20 μm. [Figure 8I] 13 is an image of pigmented iPSC-derived RPE cells. [Figure 8J] Figure 1 shows the effect of elamipretide (309) and compound of formula IIa (146c) on iPSC-derived RPE cell viability in nitrite-modified ECM. *p<0.05. [Figure 8K] 1 is a heatmap showing hierarchical cluster analysis (HCA) of AMD-derived RPE cells cultured in nitrite-modified ECM versus AMD-derived RPE cultured in unmodified ECM. [Figure 8L] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8M]1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8N] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8O] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8P] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8Q] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8R] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8S] 1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8T]1 is a graph showing the effect of elamipretide (309) and compound of formula IIa (146c) on complement-related gene expression in AMD-derived RPE cells cultured in an in vitro Bruch's membrane model. From left to right in each graph, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite 146c 10 nM, AMD nitrite 146c 100 nM, AMD nitrite 146c 1000 nM, AMD nitrite 309 10 nM, AMD nitrite 309 100 nM, and AMD nitrite 309 1000 nM. [Figure 8U] 13 is a heatmap showing the HCA of 13 mitochondrial-encoded genes in AMD-derived RPE cells cultured on nitrite-modified versus unmodified ECM. [Figure 8V] 13 is a heatmap showing the HCA of 293 mitochondrial-related genes in AMD-derived RPE cells cultured on nitrite-modified versus unmodified ECM. [Figure 8W] FIG. 1 shows the effect of elamipretide (309) and compound of formula IIa (146c) on gene expression levels from mitochondria-related genes. From left to right in each diagram, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite146c 10 nM, AMD nitrite146c 100 nM, AMD nitrite146c 1000 nM, AMD nitrite309 10 nM, AMD nitrite309 100 nM, and AMD nitrite309 1000 nM. [Figure 8X] FIG. 1 shows the effect of elamipretide (309) and compound of formula IIa (146c) on gene expression levels from mitochondria-related genes. From left to right in each diagram, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite146c 10 nM, AMD nitrite146c 100 nM, AMD nitrite146c 1000 nM, AMD nitrite309 10 nM, AMD nitrite309 100 nM, and AMD nitrite309 1000 nM. [Figure 8Y]FIG. 1 shows the effect of elamipretide (309) and compound of formula IIa (146c) on gene expression levels from mitochondria-related genes. From left to right in each diagram, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite146c 10 nM, AMD nitrite146c 100 nM, AMD nitrite146c 1000 nM, AMD nitrite309 10 nM, AMD nitrite309 100 nM, and AMD nitrite309 1000 nM. [Figure 8Z] FIG. 1 shows the effect of elamipretide (309) and compound of formula IIa (146c) on gene expression levels from mitochondria-related genes. From left to right in each diagram, the following groups are shown: AMD-unmodified, AMD nitrite, AMD nitrite146c 10 nM, AMD nitrite146c 100 nM, AMD nitrite146c 1000 nM, AMD nitrite309 10 nM, AMD nitrite309 100 nM, and AMD nitrite309 1000 nM. [Figure 8AA] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AB] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AC] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8A-D]8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AE] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AF] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8A-G] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AH] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AI] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AJ]8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AK] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 8AL] 8A-8A are graphs showing the effect of elamipretide (309) and compound of formula IIa (146c) on mitochondrial function in patient-derived RPE cells: ATP production (FIGS. 8AA-8AC), basal respiration (FIGS. 8AD-8AF), maximal respiration (FIGS. 8AG-8AI), and spare respiratory capacity (FIGS. 8AJ-8AL). [Figure 9] FIG. 1 illustrates the daily rotation of injection sites as described in Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] It should be understood that certain aspects, modes, embodiments, variations and features of the present technology are described below at various levels of detail to provide a substantial understanding of the present technology. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the present technology belongs.

[0042] The practice of the present technology employs many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology, and recombinant DNA, which are well known and described, for example, in: Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997), Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989), DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed. (1985), Oligonucleotide, respectively. Synthesis, Gait, Ed. (1984), Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985), Transcription and Translation, Hames & Higgins, Eds. (1984), Animal Cell Culture, Freshney, Ed. (1986), Immobilized Cells and Enzymes (IRL Press, 1986), Perbal, A Practical Guide to Molecular Cloning, the series, Meth. Enzymol., (Academic Press, Inc., 1984), Gene Transfer Vectors for Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, NY, 1987), and Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds.

[0043] Definition: Definitions of certain terms used herein are provided below: Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs.

[0044] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, and the like.

[0045] As used herein, "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to those of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the recited value.

[0046] As used herein, "administration" of an agent, drug, therapeutic agent, peptide or peptidomimetic to a subject includes any route of introducing or delivering a compound, composition, or formulation to a subject to perform its intended function. Administration may be by any suitable route, such as oral administration. Administration may be subcutaneous. Administration may be intravitreal. Administration may be topical. Administration may be intraocular. Administration may be ocular. Administration may be systemic. Alternatively, administration may be intranasal, intravenous, intraperitoneal, intradermal, intrathecal, intraventricular, iontophoretic, transmucosal, intravitreal, or intramuscular. Administration includes self-administration and administration by another.

[0047] As used herein, "ameliorating" or "ameliorating" a disease, disorder, or condition in a statistical sample or particular subject refers to the result of making the occurrence of a disease, disorder, or condition (or a sign, symptom, or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent compared to a control sample or subject.

[0048] As used herein, the term "amino acid" includes naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. The term "amino acid" includes both isolated amino acid molecules (i.e., molecules that contain both the amino-bound hydrogen and the carbonyl carbon-bound hydroxyl) and residues of amino acids (i.e., molecules in which either one or both of the amino-bound hydrogen or the carbonyl carbon-bound hydroxyl have been removed), unless otherwise indicated. The amino group may be an alpha amino group, a beta amino group, and the like. For example, the term "amino acid alanine" can refer to isolated alanine H-Ala-OH, or any one of the alanine residues H-Ala-, -Ala-OH, or -Ala-. Unless otherwise indicated, all amino acids found in the compounds described herein may be in either the D or L configuration. Amino acids in the D configuration may be written such that a "D" precedes the abbreviation for the amino acid. For example, "D-Arg" represents arginine in the D configuration. The term "amino acid" includes salts thereof, including pharma- ceutically acceptable salts. Any amino acid can be protected or unprotected. Protecting groups can be attached to the amino group (e.g., the alpha amino group), the backbone carboxyl group, or any functional group of the side chain. As an example, phenylalanine protected by a benzyloxycarbonyl group (Z) on the alpha amino group would be represented as Z-Phe-OH. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. An amino acid analog refers to a compound that has the same basic chemical structure as a naturally occurring amino acid (i.e., an α carbon attached to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium). Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0049] The terms "DMT", "Dmt", "2',6'-DMT", or "2',6'-Dmt" refer to 2,6-di(methyl)tyrosine (e.g., 2,6-dimethyl-L-tyrosine, CAS 123715-02-6).

[0050] As used herein, the phrase "delaying the onset of" refers to postponing, preventing the onset of, or causing one or more signs or symptoms of, a disease, disorder, or condition to occur later than normal in a statistical sample in a sample or subject administered a therapeutic agent compared to a control sample or subject.

[0051] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount that results in the prevention, reduction, or delay of onset of symptoms associated with an ocular condition. The amount of the composition administered to a subject will depend on the type and severity of the disease, as well as individual characteristics such as general health, age, sex, weight, and tolerance to drugs. It will also depend on the extent, severity, and type of disease. One of skill in the art will be able to determine appropriate dosages depending on these and other factors. The composition can also be administered in combination with one or more additional therapeutic agents / compounds. In the methods described herein, the peptidomimetic can be administered to a subject having one or more signs or symptoms of an ocular condition. For example, a "therapeutically effective amount" of a peptidomimetic refers to a level at which the physiological effects of an ocular condition are, at a minimum, ameliorated or delayed in progression and / or severity.

[0052] As used herein, the term "hydrate" refers to a compound associated with water. The number of water molecules contained in a hydrate of a compound may (or may not) be in a definite ratio to the number of compound molecules in the hydrate.

[0053] As used herein, "inhibit" or "inhibiting" refers to a reduction in a sign, symptom, or condition (e.g., a risk factor) associated with a disease, disorder, or condition by an objectively measurable amount or extent compared to a control. In one embodiment, inhibit or inhibiting refers to a reduction to at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction to at least a 5 percent reduction compared to a control (or control subject). In various individual embodiments, inhibit or inhibiting refers to a reduction to at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent reduction compared to a control (or control subject).

[0054] As used herein, the term "peptidomimetic" refers to a small peptide-like polymer that contains two or more amino acids, but also contains non-peptide-like modifications. Peptidomimetics can arise by modification of existing peptides or by designing similar molecules that mimic peptide function. In some embodiments, the peptidomimetic has formula I, II, IIa, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, as defined herein, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof.

[0055] As used herein, "prevention" or "preventing" of a disease, disorder, or condition refers to a result in a statistical sample that shows a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent compared to a control sample or subject, or a delay in the onset of one or more symptoms of the disease, disorder, or condition relative to a control sample or subject. Such prevention is sometimes referred to as prophylactic treatment.

[0056] The terms "pharmaceutical acceptable carrier" and "carrier" as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutical acceptable carriers include liquids such as water, saline, and oils, and solids such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein by reference in its entirety.

[0057] As used herein, the term "pharmaceutical acceptable salts" refers to salts of therapeutically active compounds that can be prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of pharmaceutical acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Salts derived from pharmaceutical acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharma- ceutically acceptable organic bases include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, trimethylamine (NEt 3 ), trimethylamine, tripropylamine, tromethamine, and other organic bases in their protonated form (e.g., [HNEt 3 ] +), including salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like. Salts derived from pharmaceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (hydrobromic acid, hydrochloric acid, hydrofluoric acid, or hydroiodic acid), nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid, and triphenylacetic acid), aromatic hydroxyl acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene acid, 1-hydroxybenzoic ... Examples of suitable carboxylic acids include naphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric, maleic, oxalic, and succinic acids), glucuronic, mandelic, mucilaginous, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acid (PTSA)), and xinafoic acid. In some embodiments, the pharma- ceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.In some embodiments, the salt is a tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or tosylate. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present application may contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts, or may exist in zwitterionic form. These salts can be prepared by methods known to those skilled in the art. Other pharma-ceutically acceptable carriers known to those skilled in the art are also suitable for the present technology.

[0058] In the context of therapeutic use or administration, the terms "separate" or "separately" refer to the administration of at least two active ingredients by different routes, formulations, and / or pharmaceutical compositions.

[0059] As used herein, the term "separate" therapeutic use refers to the administration of at least two active ingredients by different routes at the same time or substantially the same time.

[0060] As used herein, the term "sequential" therapeutic use refers to the administration of at least two active ingredients at different times, and the administration route is the same or different. More specifically, sequential use refers to the administration of one of the active ingredients entirely before the administration of the other(s) is started. Thus, one of the active ingredients can be administered minutes, hours, or days before the administration of the other active ingredient(s). In this case, there is no simultaneous treatment.

[0061] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or substantially the same time.

[0062] As used herein, the term "solvate" refers to a form of a compound (e.g., a peptide or peptidomimetic) that is associated with a solvent, usually via a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like.

[0063] As used herein, the terms "subject" and "patient" are used interchangeably.

[0064] As used herein, a "synergistic therapeutic effect" refers to a greater than additive therapeutic effect produced by the combination of at least two agents that exceeds the otherwise resulting from administration of the agents individually. For example, lower doses of one or more agents may be used in the treatment of ALS, alpha-synucleinopathies, or TDP-43 proteinopathies, resulting in increased therapeutic efficacy and reduced side effects.

[0065] As used herein, the term "tautomers" refers to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0066] As used herein, "treating" or "treatment" or "alleviation" refers to therapeutic treatment, the purpose of which is to reduce, alleviate, or delay (attenuate) an existing disease or disorder, or its associated signs, symptoms, or conditions. By way of example, and not by way of limitation, a subject is successfully "treated" for a disease if, after receiving an effective amount of a compound / composition / drug product, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, the subject shows an observable and / or measurable reduction, or absence, of one or more signs, symptoms, or conditions associated with the disease, disorder, or condition. It should also be recognized that the various modes of treatment of the described medical conditions are intended to mean "substantial," including the overall alleviation of the condition, signs, or symptoms of the disease or disorder, as well as "partial," in which some biologically or medically relevant result is achieved.

[0067] As used herein, "(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide", "(D-Arg-DMT-NH ..." The terms "compound 7a" and "7a" refer to the same peptidomimetic and are used interchangeably herein, and refer to a compound of formula II: [ka]

[0068] "(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide"; (2R)-2-amino-N-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl]amino] The terms D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pent-1-yl), ... [ka]

[0069] Peptide mimetics: In some embodiments, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R2a teeth, [ka] is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0070] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] It is. In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] In some embodiments, AA 1 teeth, [ka] It is.

[0071] In some embodiments, AA 2 teeth, [ka] Some embodiments are 2 teeth, [ka] In some embodiments, AA 2 teeth, [ka] It is.

[0072] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is. In some embodiments, R 1 teeth, [ka] It is. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is.

[0073] In some embodiments, R 2a teeth, [ka] In some embodiments, R 2a teeth, [ka] It is. In some embodiments, R 2a teeth, [ka] In some embodiments, R 2a teeth, [ka] In some embodiments, R 2a teeth, [ka] It is. In some embodiments, R 2a teeth, [ka] It is. In some embodiments, R 2a teeth, [ka] It is.

[0074] In some embodiments, R 2b is H. In some embodiments, R 2b is methyl.

[0075] In some embodiments, R 3 is H. In some embodiments, R 3 is (C 1 -C 6 ) alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 3 is methyl. In some embodiments, R 3 is ethyl.

[0076] In some embodiments, R 4 is H. In some embodiments, R 4 is (C 1 -C 6 ) alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 4 is methyl. In some embodiments, R 4 is ethyl.

[0077] In some embodiments, R 3 and R 4 are the same. In some embodiments, R 3 and R 4 is different.

[0078] In some embodiments, R 5 is H. In some embodiments, R 5 is methyl.

[0079] In some embodiments, R 6 is H. In some embodiments, R 6 is methyl.

[0080] In some embodiments, R 5 and R 6 are the same. In some embodiments, R 5 and R 6 is different.

[0081] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.

[0082] In some embodiments, R 7 is H. In some embodiments, R 7 is (C 1 -C 6 ) alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 7 is methyl.

[0083] In some embodiments, R 7 is cycloalkyl. In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 7 is aryl. In some embodiments, R 7 is phenyl.

[0084] In some embodiments, R 8 is H. In some embodiments, R 8 is (C 1 -C 6 ) alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 8 is methyl. In some embodiments, R 8 is ethyl.

[0085] In some embodiments, R 8 is cycloalkyl. In some embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 8 is aryl. In some embodiments, R 8 is phenyl.

[0086] In some embodiments, R 9 is H. In some embodiments, R 9 is (C 1 -C 6 ) alkyl. In some embodiments, R 9 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 9 is methyl. In some embodiments, R 9 is ethyl.

[0087] In some embodiments, R 9 is cycloalkyl. In some embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 9is aryl. In some embodiments, R 9 is phenyl.

[0088] In some embodiments, R 8 and R 9 are the same. In some embodiments, R 8 and R 9 is different.

[0089] In some embodiments, R 8 and R 9 together with the N atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.

[0090] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] It is.

[0091] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, p is 0. In some embodiments, p is 1.

[0092] In some embodiments, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] Selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H and R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 are independently H or methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is [ka] is selected from.

[0093] In some embodiments, AA 1 teeth, [ka] and A.A. 2 teeth, [ka] and R 1 teeth, [ka] and R 2a teeth, [ka] and R 7 is H and X is [ka] It is.

[0094] In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV, [ka] [ka] or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0095] In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the molecule are optionally replaced with a deuterium or fluorine atom.

[0096] The chiral centers of the peptidomimetics disclosed herein may be in either the R or S configuration, as discussed in more detail below.

[0097] Chiral / Stereochemical Considerations The peptidomimetics described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Additionally, peptidomimetics encompass the compounds described herein as individual isomers substantially free of other isomers, or alternatively as mixtures of various isomers.

[0098] As used herein, a pure enantiomer peptidomimetic is substantially free of other enantiomers or stereoisomers of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. With respect to amino acids (more commonly described in terms of "D" and "L" enantiomers), it should be understood that for "D" amino acids, the configuration is "R" and for "L" amino acids, the configuration is "S" (except for cysteine, where the assignment is reversed due to the presence of sulfur in the side chain). In some embodiments, "substantially free" refers to: (i) an aliquot of an "R" form compound that contains less than 2% of the "S" form, or (ii) an aliquot of an "S" form compound that contains less than 2% of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0099] In the compositions provided herein, the enantiomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure "R" compound may comprise, for example, about 90% of an excipient and about 10% of an enantiomerically pure "R" compound. In certain embodiments, the enantiomerically pure "R" compound in such a composition may comprise, for example, at least about 95% by weight of the "R" compound and up to about 5% by weight of the "S" compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure "S" compound may comprise, for example, about 90% of an excipient and about 10% of the enantiomerically pure "S" compound. In certain embodiments, the enantiomerically pure "S" compound in such a composition may comprise, for example, at least about 95% by weight of the "S" compound and up to about 5% by weight of the "R" compound, based on the total weight of the compound. In certain embodiments, the active ingredients can be formulated with few or no excipients or carriers.

[0100] The nomenclature used to define the peptide compounds described herein is that used in the art, where the N-terminal amino group typically appears on the left and the C-terminal carboxyl group appears on the right, with the exception that the peptidomimetics disclosed herein do not contain a carboxylic acid or amide moiety at the C-terminus.

[0101] The capital letter "D" used in conjunction with an abbreviation for an amino acid residue refers to the D-form of the amino acid residue. For example, D-Arg is a commercially available D-amino acid.

[0102] The peptidomimetics disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms may exist, for example, because it is difficult or impossible to remove all of the solvent from the peptidomimetic after synthesis. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present application. Certain peptidomimetics of the present application may exist in multiple crystalline or amorphous forms. Certain peptidomimetics of the present application may exist in various tautomeric forms. Certain peptidomimetics of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are contemplated to be within the scope of the present application.

[0103] In some embodiments, the peptidomimetic disclosed herein is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (II), or a pharma- ceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, and the subject has been diagnosed with an ocular condition or disease. In some embodiments of the peptidomimetics of the present technology, treating or preventing includes treating or preventing macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataracts, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), Leber's congenital amaurosis (LCA), or treating or preventing in a mammalian subject. In some embodiments, the subject is a human.

[0104] In some embodiments of the peptidomimetics of the present technology, the peptidomimetics are administered to a subject (either neat or in a formulation or medicament) separately, sequentially, or simultaneously with an additional therapeutic agent or additional therapeutic treatment. In some embodiments, the additional therapeutic agent is selected from the group consisting of antioxidants, metal complexing agents, anti-inflammatory agents, antibiotics, and antihistamines. In one embodiment, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, alpha-lipoic acid, coenzyme Q, glutathione, or a carotenoid.In one embodiment, the therapeutic agent is aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demecarium, dexamethasone ... Samethasone, diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurane, ketorolac, ketotifen, latanopeptide Lost, levobetaxolol, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, Further comprising an active agent selected from the group consisting of ranibizumab, rimexolone, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinuron, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarubine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations of two or more of the foregoing.In some embodiments, the additional therapeutic agent is carbatiol (Carbastat® or Carboptic®), polocarpine (Salagen®), timolol (Timoptic®), betaxolol (Betoptic® or Keflone®), carteolol (Cartrol® or Ocupress®), levobunolol (Liquifilm®), brimonidine (Lumify® or Mirvaso®), apraclonidine (Iopidine®), latanoprost (Xalantan®), travoprost (Travatan®), or cefotaxime (Citrolev®). These include, but are not limited to, acetazolamide (Diamox®), methazolamide (Neptazane®), brimonidine tartrate / timolol maleate (Combigan®), timolodorzolamide (Cosopt®), travoprost-timolol (DuoTrav®), and latanoprost and timolol maleate (Xalacom®).

[0105] Synthesis of peptidomimetics: The peptidomimetic compounds of the present technology can be prepared in whole or in part using peptide synthesis methods such as conventional liquid phase (also known as solution phase) or solid phase peptide synthesis, or by peptide synthesis with an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and Methods, Setlow, JKeds., Plenum Press NY. (1990) Vol. 12, pp. 1 to 19; Stewart et al., Solid-Phase Peptide Synthesis (1989) WH; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p. 5132). The peptidomimetics thus produced can be collected or purified by conventional methods, such as chromatography, such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reverse phase column chromatography, and HPLC, ammonium sulfate fractionation, ultrafiltration, and immunoadsorption. For example, the peptidomimetics described herein can be prepared as described in WO2019 / 118878, entitled Mitochondrial-Targeting Peptides.

[0106] In solid-phase peptide synthesis, peptides are typically synthesized from the carbonyl group (C-terminus) to the amino group (N-terminus) of the amino acid chain. In certain embodiments, an amino-protected amino acid is covalently attached to a solid support material through the carboxyl group of the amino acid, typically through an ester or amide bond, and optionally through a linking group. The amino group may be deprotected and reacted (i.e., "coupled") with the carbonyl group of a second amino-protected amino acid using a coupling reagent to generate a dipeptide bound to the solid support. After coupling, the resin is optionally treated with a capping reagent, thereby capping any unreacted amine groups (making them inactive toward the subsequent coupling step). These steps (i.e., deprotection, coupling, and optionally capping) may be repeated to form the desired peptide chain. Once the desired peptide chain is complete, the peptide may be cleaved from the solid support.

[0107] In certain embodiments, protecting groups used for amino groups of amino acid residues (peptides and / or peptidomimetics) include 9-fluorenylmethyloxycarbonyl (Fmoc) and t-butyloxycarbonyl (Boc). The Fmoc group is removed from the amino terminus with base and the Boc group is removed with acid. In an alternative embodiment, the amino protecting group is a substituted or unsubstituted group of the aralkyloxycarbonyl type, such as formyl, acrylyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2(p-biphenylyl)isopropyloxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group (Fmoc), tert-butyloxycarbonyl (BOC), tert-amyloxycarbonyl, tert-butyloxycarbonyl (BOC), tert-amyloxycarbonyl, tert-butyloxycarbonyl (BZ), ... It may be a substituted or unsubstituted radical of the alkyloxycarbonyl type, such as the oxycarbonyl, diisopropylmethyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, 2-methylsulfonylethyloxycarbonyl or 2,2,2-trichloroethyloxycarbonyl radical, a radical of the cycloalkyloxycarbonyl type, such as the cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl radical, and a radical containing a heteroatom, such as the benzenesulfonyl, p-toluenesulfonyl, mesitylenesulfonyl, methoxytrimethylphenylsulfonyl, 2-nitrobenzenesulfonyl, 2-nitrobenzenesulfenyl, 4-nitrobenzenesulfenyl or 4-nitrobenzenesulfenyl radical.

[0108] Many amino acids have reactive functional groups in their side chains. In certain embodiments, such functional groups are protected to prevent the functional groups from reacting with the incoming amino acid. The protecting groups used with these functional groups must be stable to the conditions of peptide and / or peptidomimetic synthesis, but can be removed before, after, or concomitantly with the cleavage of the peptide from the solid support (if support-bound), or during final deprotection in the case of solution-phase synthesis. Also see: Isidro-Llobet, A., Alvarez, M., Albericio, F., "Amino Acid-Protecting Groups"; Chem. Rev., 109:2455-2504 (2009) for a comprehensive review of protecting groups commonly used in peptide synthesis (which protecting groups can also be used in peptidomimetic synthesis where the peptidomimetic contains functional groups found in peptides).

[0109] In certain embodiments, the solid support material used in solid phase peptide synthesis methods is a gel-type support such as polystyrene, polyacrylamide, or polyethylene glycol. Alternatively, materials such as controlled pore glass, cellulose fibers, or polystyrene can be functionalized on their surfaces to provide solid supports for peptide synthesis.

[0110] The coupling reagents that can be used in the solid phase (or solution phase) peptide synthesis described herein are typically carbodiimide reagents. Examples of carbodiimide reagents include, but are not limited to, N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and its HCl salt (EDC HCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), N,N'-diisopropylcarbodiimide (DIC), N-tert-butyl-N'-methylcarbodiimide (BMC), N-tert-butyl-N'-ethylcarbodiimide (BEC), bis[[4-[(2,2-dimethyl-1,3-dioxolyl)]-methyl]carbodiimide (BDDC), and N,N-dicylopentylcarbodiimide. DCC is the preferred coupling reagent. Other coupling reagents include (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), typically used in combination with an organic base such as N,N-diisopropylethylamine (DIEA) and a hindered pyridine-type base such as lutidine or collidine.

[0111] In some embodiments, amino acids can be activated for coupling to a peptide or peptidomimetic by forming an N-carboxyanhydride, as described in Fuller et al., Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Peptide Synthesis, Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018 / 034901.

[0112] In certain exemplary embodiments, compounds useful in the therapeutic methods described herein can be synthesized in a convergent manner according to the solid phase synthesis depicted in Scheme 1. For reference in the schemes below: [ka] teeth, [ka] indicates, [ka] represents a solid support and optionally a linking group. [ka]

[0113] For example, the compounds shown below may be synthesized by such a method as shown in Scheme 2. [ka]

[0114] Scheme 2 For reference in the schemes below: [ka] teeth, [ka] indicates, [ka] represents a solid support and optionally a linking group. [ka]

[0115] The compounds of the present technology can also be synthesized according to conventional solution phase peptide synthesis routes, for example, Scheme 3. [ka]

[0116] For example, the compounds shown below may be synthesized by such a method as shown in Scheme 4. [ka] [ka]

[0117] Synthesis of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pent-1-yl), 7a) (also known as (Formula IIa)), In some embodiments, compound 7a (also known as formula IIa) can be synthesized as shown in Scheme 5 below (see also WO2019 / 118878, which is incorporated herein by reference). Compound 12a can be prepared as shown in Scheme 6 below. [ka] compound 7a [ka]

[0118] Step a: Synthesis of (S)-2-((R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanamido)-3-(4-hydroxy-2,6-dimethylphenyl)propanoate (3a). 2,6-Dmt-OBn in ACN . To a suspension (800 mL) of HCl (2a, 45.0 g, 134 mmol), NMM (32.7 mL, 298 mmol) was added at 0° C. The reaction mixture was stirred until the reaction mixture became clear. Then, Boc-D-Arg-OH .HCl (1a, 46.3 g, 149 mmol) and HOBt . H 2 O (9.11 g, 59.5 mmol) was added to the reaction mixture and stirred for 15 min. Finally, EDC . HCl (38.5 g, 201 mmol) was added and the mixture was stirred at 0° C. for 4 h. Then, EtOAc (450 mL), 1N HCl in brine (300 mL) were added. The combined organic extracts were washed with 1N HCl in brine (7×150 mL), NaHCO 3 / brine (300 mL, and until the pH of the aqueous layer is about pH = 6-7), and then Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 86.0 g (97%) of Boc-D-Arg-DMT-OBn (3a), which was used without further purification. 1 H-NMR (400 MHz, methanol-d 4 )δ7.33-7.18(m, 5H), 6.43(s, 2H), 5.06(s, 2H)4.71(t, J=7.8Hz, 1H), 4.07(t, J=6.7Hz,1H), 3.19 -3.09(m, 3H), 3.03-2.97(m, 1H), 2.23(s, 6H), 1.72-1.65(m, 1H), 1.54-1.43(m, 3H), 1.45(s, 9H).

[0119] Step b: Synthesis of (S)-2-((R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanamido)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid (4a). To a solution of Boc-D-Arg-DM-Tyr-OBn (3a, 84.0 g, 142 mmol) in MeOH (1000 mL) was added Pd / C (10% w / w, 14.0 g). Hydrogen was purged into the reaction mixture at room temperature for 4 h. The reaction mixture was then filtered through filter paper and washed with MeOH (150 mL). The solvent was removed by evaporation. The white foam product 4a was obtained (74.0 g, 93%) and used without further purification. 1 H-NMR (400 MHz, methanol-d 4)δ6.44(s, 2H), 4.68(t, J=7.2Hz, 1H), 4.04(t, J=6.8Hz, 1H), 3.15-3.09(m, 3H), 3 .02-2.94(m, 1H), 2.29(s, 6H), 1.74-1.59(m, 1H), 1.54-1.43(m, 1H), 1.45(s, 9H).

[0120] Step c: Synthesis of tert-butyl ((6R,9S,12S)-1-amino-12-(3-benzyl-1,2,4-oxadiazol-5-yl)-9-(4-hydroxy-2,6-dimethylbenzyl)-1-imino-20,20-dimethyl-7,10,18-trioxo-19-oxa-2,8,11,17-tetraazahenicosan-6-yl)carbamate (6a). DMF (200 mL) was added to 4a (11.17 g, 24 mmol) and stirred at room temperature for 15 min. To the resulting suspension was added 12a (10.65 g, 20 mmol) and stirred at room temperature for 20 min. After addition of HOBt (612 mg, 4.00 mmol), the suspension was cooled in an ice bath. EDC·HCl (5.38 g, 28 mmol) was added in one portion and the reaction mixture was stirred for 2.5 h with cooling in an ice bath and then for 4.5 h at room temperature. The nearly homogeneous reaction mixture was quenched with EtOAc (1500 mL) and the resulting solution was washed ten times with brine / aqueous 0.5 M HCl (1:1, 400 mL). During the sixth and ninth washes, a gel formed in the aqueous phase. After addition of iPrOH (40 mL in each case) and repeated shaking, the layers became clear again. The organic phase was then washed with brine / NaHCO 3 It was washed six times with saturated aqueous solution (9:1, 400 mL). During the fourth wash, a gel formed in the aqueous phase. After adding iPrOH (40 mL) and repeated shaking, the layers separated easily. The organic phase was washed with brine (200 mL) and water (100 mL), and the solvent was removed under reduced pressure. Vigorous shaking was not performed during the water washes to avoid difficult phase separation. As a result, 16.8 g of crude product was obtained (6a, 97.0% purity by HPLC, white amorphous solid). 1 H-NMR (300 MHz, methanol-d 4)ppm:δ=7.33-7.16(m, 5H), 6.38(s, 2H), 5.18-5.07(m, 1H), 4.64-4.55(m, 1H), 4.10-3.92(m, 3H) , 3.18-2.77(m, 6H), 2.20(s, 6H), 1.97-1.76(m, 2H), 1.75-1.14(m, 8H), 1.43(s, 9H), 1.41(s, 9H).

[0121] Step d: Synthesis of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (7a, also referred to herein as (IIa - trihydrochloride salt of compound I)). After dissolving 6a (16.8 g) in DCM (100 mL) and cooling to 0° C., TFA (20 mL) was added dropwise and the solution was stirred at 0° C. for 10 min and then at room temperature for 3 h (LC / MS shows no starting material). The reaction mixture was then evaporated (0-5° C.) and additionally re-evaporated from DCM (100 mL, 0-5° C.). Purification by reversed-phase flash chromatography (cartridge C-18, 120G) was carried out on the crude material in four portions. Then all the solvents were evaporated under reduced pressure at <40°C. The white foam was dissolved in isopropanol (100 mL) and 5 mL of HCl (5-6 M) in isopropanol was added at 0°C and evaporated under reduced pressure. This step was repeated three times. Additionally, 100 mL of ACN was added and the suspension was evaporated once more. As a result, a white powder of 7a was obtained as the trihydrochloride salt. 1 H-NMR (300 MHz, methanol-d 4)δ7.36-7.14(m, 5H), 6.40(s, 2H), 5.15(dd, J=8.5, 6.3Hz, 1H), 4.68(dd, J=8.7, 7.5Hz, 1H), 4.07(s, 2H), 3.97(t, J=6.3Hz, 1H) ), 3.18(t, J=6.9Hz, 2H), 3.11(dd, J=14.2, 8.8Hz, 1H), 2.95-2.84(m, 3H), 2.22(s, 6H), 2.02-1.59(m, 6H), 1.57-1.28(m, 4H). MS:EI-MS:m / z608.4[M+1].

[0122] Synthesis of (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentan-1-aminium 4-methylbenzenesulfonate (12a) [ka] Step a: NH 2 OH, Step b: T 3 P, NaHCO 3 , Step c: TEA, Step d: PTSA Step a: Synthesis of N-hydroxy-2-phenylacetimidamide (9a). A solution of nitrile 8a (1.0 mol) in EtOH (1.2 L) was added with NH 2 OH (50% in water, 130 g, 2.0 mol) was added. The solution was heated to reflux and stirred for 12 hours (hrs.). Upon completion, the reaction mixture was concentrated under reduced pressure. The resulting residue was redissolved in EtOH (350 mL) and concentrated again under reduced pressure (this procedure was repeated three times). The resulting solid was triturated in hexane (350 mL), filtered, washed with hexane (100 mL) and then dried to give the desired product 9a as a white solid. (10.5 kg, KF=1295) with good results (purity by HPLC, >98.9A%, assay=22.2w%, yield=91%). 1 H NMR (300 MHz, DMSO-d 6 ): δ8.90(s, 1H), 7.28-7.18(m, 5H), 5.40(s, 2H), 3.25(s, 2H)ppm. MS:(M+H) +: m / z=151.1

[0123] Step b: Synthesis of (9H-fluoren-9-yl)methyl tert-butyl(1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(S)-dicarbamate (11a). To a solution of protected enantiomerically pure N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (10a, 4.31 kg, 9.2 mol) and hydroxyimidamide 9a (1.1 equivalents “equiv.” or “eq.”) in ethyl acetate was added NaHCO 3 (3.0 equiv.) was added. The mixture was stirred at 25° C. for 20 minutes (min.). Then, propanephosphonic anhydride (T 3 P, 50% solution in ethyl acetate, 3.0 equivalents (equiv.) was added and the reaction mixture was heated to 80° C. and stirred for 4 hours (conversion of compound 10a was about 60% based on HPLC). Compound 9a (1.1 equivalents) was then added and the reaction mixture was stirred at 80° C. for an additional 20 hours (about 10% of compound 10a remained). The reaction mixture was cooled to room temperature and NaHCO 3 Saturated aqueous solution (2.0 L) was added and the mixture was extracted with ethyl acetate (3×1.0 L). The combined organic layers were then washed with brine (1 L). 、 Anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave a crude residue which was generally purified by silica gel column chromatography (petroleum ether (PE):EtOAc=5:1) to give the crude product, (9H-fluoren-9-yl)methyl tert-butyl (1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl) (S)-dicarbamate (11a), solution in ACN (19.7 kg, assay=20%, chiral HPLC purity=99.12A%, yield=73%). 1 H-NMR (300 MHz, CDCl 3):δ7.78(d, J=7.5Hz, 2H), 7.61(d, J=6.3Hz, 2H), 7.42(t, J=7.5Hz, 2H), 7.35-7.30(m, 7H), 5.52(br, 1H), 5.09- 5.05(m, 1H), 4.56-4.37(m, 3H), 4.22(t, J=6.6Hz, 1H), 4.08(s, 2H), 1.95-1.86(m, 2H), 1.48-1.42(m, 11H)ppm. MS:(M-100+H) + : m / z = 483.2.

[0124] Step c: Synthesis of tert-butyl (S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a). To a solution of compound (9H-fluoren-9-yl)methyl tert-butyl (1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl) (S)-dicarbamate (11a), TEA (2.5 equiv.) was added. The mixture was stirred with a mechanical stirrer at 20-25 °C for 15 h. The reaction mixture was diluted with tap water and MTBE. The separated aqueous layer was extracted once with MTBE. Both MTBE layers were combined and then diluted with NH 4 Cl. Then, it was washed with anhydrous Na 2 SO 4 was added and the solution was stirred for at least 2 hours, then filtered and washed with MTBE to give tert-butyl (S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a) in MTBE (32.9 kg, assay=6.5%, yield=88%). 1 H-NMR (300 MHz, DMSO-d 6 ):δ7.33-7.25(m, 5H), 6.78(br, 1H), 5.09-5.05(m, 1H), 4.56-4.37(m, 3H), 4.06(s, 2H), 3.98(t, J= 6.6Hz, 1H), 2.87-2.84(m, 2H), 2.10(s, 2H), 1.38-1.34(m, 2H), 1.24(s, 9H), 1.20-1.15(m, 2H)ppm. MS:(M+H) + : m / z=361.1.

[0125] Step d: Synthesis of (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentan-1-aminium 4-methylbenzenesulfonate (12a). p-Toluenesulfonic acid (PTSA) was added to a solution of crude tert-butyl (S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a) in MTBE to give (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentan-1-aminium 4-methylbenzenesulfonate (12a) as a white solid (2.7 kg, yield=85%, HPLC purity>99%, ee>99%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ8.74(br, 3H), 7.48(d, J=8.0Hz, 2H), 7.37-7.26(m, 5H), 7.11(d, J=8.0Hz, 2H), 6.77(t, J=5.2Hz, 1H), 4. 82(t, J=6.8Hz, 1H), 4,17(s, 2H), 2.90-2.86(m, 2H), 2.29(s, 3H), 1.39-1.36(m, 11H), 1.35-1.28(m, 2H)ppm. MS:(M-172+H) + : m / z=361.1.

[0126] Treatment method One aspect of the present technology includes a method useful for treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject. Thus, in one aspect, the method provides for management of an ocular disease, disorder, or condition in a subject by administering to a subject in need thereof an effective amount of a peptidomimetic, such as a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof. For example, a subject may be administered the peptidomimetic (or a composition, formulation, or medicament comprising the peptidomimetic) in an effort to ameliorate one or more of the factors or aspects involved in an ocular disease, disorder, or condition, such as macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataracts, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA). The disease, disorder, or condition may also be geometric atrophy (GA). The disease, disorder, or condition may also be drusen. The disease, disorder, or condition may also be glaucoma.

[0127] As discussed above, the ellipsoid zone (EZ) of the eye is rich in mitochondria. The peptidomimetics disclosed herein target mitochondria. The peptidomimetics disclosed herein can penetrate the eye (and its various compartments / parts, such as choroid, ciliary body, cornea, fovea, iris, lens, macula, optic nerve, pupil, retina, sclera, and vitreous humor), as demonstrated for the compound of formula II in Example 1. Thus, in another aspect, the peptidomimetics disclosed herein are potentially highly beneficial drugs for use in the treatment and management of ocular diseases, disorders, and conditions, particularly those that affect the ellipsoid zone, as demonstrated by Example 2 below. Thus, the present method can also provide for the management of ellipsoid zone deterioration (i.e., deterioration or ellipsoid zone health) in one or more eyes of a mammalian subject.

[0128] Thus, one aspect of the present technology includes a method for treating an ocular disease, disorder, or condition of a subject for therapeutic purposes.In therapeutic applications, a compound, composition, formulation, or drug can be administered to a subject suspected of or already suffering from such a disease, disorder, or condition in an amount sufficient to cure or at least partially halt the symptoms of the disease, including complications and pathological phenotypes that mediate in the development of the disease.Thus, the present disclosure provides a method for managing an individual suffering from an ocular disease, disorder, or condition.

[0129] Thus, in one embodiment, the present technology relates to a method of treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (i.e., Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] Selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl, R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, m is 1, 2, or 3, n is 1, 2, or 3, p is 0 or 1, and X is [ka] where * is an R of X 1 and one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom. 1 teeth, [ka] Selected from AA 2 teeth, [ka] Selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H and R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is [ka] In some embodiments, AA 1 teeth, [ka] and A.A. 2 teeth, [ka] and R 1 teeth, [ka] and R 2a teeth, [ka] and R 7 is H and X is [ka] In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV, [ka] [ka] or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0130] In some embodiments, the present technology relates to a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of deterioration of ellipsoid zone health in one or more eyes of a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] Selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl, R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, m is 1, 2, or 3, n is 1, 2, or 3, p is 0 or 1, and X is [ka] where * is an R of X 1and one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom. 1 teeth, [ka] Selected from AA 2 teeth, [ka] Selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H and R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is [ka] In some embodiments, AA 1 teeth, [ka] and A.A. 2 teeth, [ka] and R 1 teeth, [ka] and R2a teeth, [ka] and R 7 is H and X is [ka] In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV, [ka] [ka] or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0131] In some embodiments, the present technology relates to a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of geometric atrophy in a mammalian subject in need thereof, the subject having been diagnosed with age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] Selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H or CH 3 and R 3 and R4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl, R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, m is 1, 2, or 3, n is 1, 2, or 3, p is 0 or 1, and X is [ka] where * is an R of X 1 and one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom. 1 teeth, [ka] Selected from AA 2 teeth, [ka] Selected from R 1 teeth, [ka] Selected from R 2a teeth, [ka] Selected from R 2b is H and R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is [ka] In some embodiments, AA 1 teeth, [ka] and A.A. 2 teeth, [ka] and R 1 teeth, [ka] and R 2a teeth, [ka] and R 7 is H and X is [ka] In some embodiments, the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV, [ka] [ka] or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0132] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject having or suspected of having macular degeneration (including, but not limited to, age-related macular degeneration). Macular degeneration is typically an age-related disease. General categories of macular degeneration include wet, dry, and non-age-related macular degeneration. Dry macular degeneration accounts for approximately 80-90% of all cases and is also known as atrophic, nonexudative, or drusenoid macular degeneration. In dry macular degeneration, drusen typically accumulate under the retinal pigment epithelium tissue. When drusen interfere with the function of photoreceptors in the macula, vision loss ensues. Symptoms of dry macular development include, but are not limited to, distorted vision, distortion of central vision, light or dark distortion, and / or changes in color vision. Dry macular degeneration can result in gradual loss of vision. Specific damage to retinal pigment epithelial (RPE) cells is a hallmark of age-related macular degeneration (AMD), and RPE cell cultures are frequently used as an in vitro model of dry AMD.

[0133] Wet macular degeneration is also known as neovascularization, subretinal neovascularization, exudative, or discoid degeneration. In wet macular degeneration, abnormal blood vessels grow under the macula. The blood vessels leak fluid into the macula and damage photoreceptor cells. Wet macular degeneration progresses quickly and can cause severe damage to central vision. Wet and dry macular degeneration have the same symptoms. However, non-age-related macular degeneration is rare and may be related to heredity, diabetes, nutritional deficiency, injury, infection, or other factors. Symptoms of non-age-related macular degeneration also include, but are not limited to, distorted vision, distortion of central vision, light or dark distortion, and / or changes in color vision.

[0134] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject who has or is suspected of having dry eye. Approximately 20 million Americans suffer from dry eye disease. People with dry eye disease produce poor quality tears and / or do not produce enough tears to provide nutrition and lubricate the cornea, resulting in eyes that appear red, are chronically irritated, gritty, and feel sore. Dry eye disease is not just about insufficient and / or poor quality tears. The condition is associated with inflammation and tissue damage, believed to be caused at least in part by oxidative stress.

[0135] In some embodiments of any of the aforementioned methods, the peptide mimetic is administered to a subject having or suspected of having diabetic retinopathy. Diabetic retinopathy is characterized by capillary microaneurysms and petechia. Microvascular occlusion then causes cotton wool spots to form in the retina. In addition, retinal edema and / or hard white spots may form in individuals with diabetic retinopathy due to increased vascular permeability. Neovascularization then appears and retinal detachment is caused by traction of the connective tissue that has grown on the vitreous. Rubeosis iridis and neovascular glaucoma may also occur, which in turn may result in blindness. Symptoms of diabetic retinopathy include, but are not limited to, difficulty reading, blurred vision, sudden loss of vision in one eye, rings seen around lights, dark spots seen, and / or flashing lights seen.

[0136] In some embodiments of any of the foregoing methods, the peptidomimetic is administered to a subject having or suspected of having diabetic macular edema, which involves damage to blood vessels in the retina that progress to the point where they leak fluid into the macula, causing the macula to swell, which results in blurred vision.

[0137] In some embodiments of any of the above methods, the peptidomimetic is administered to a subject who has or is suspected of having cataract. Cataract is a congenital or acquired disease characterized by a decrease in the transparency of the natural lens. Individuals with cataract may show one or more symptoms, including, but not limited to, clouding on the surface of the lens, clouding inside the lens, and / or swelling of the lens. Typical examples of congenital cataract-related diseases are pseudocataract, membranous cataract, coronal cataract, platy cataract, punctate cataract, and filiform cataract. Typical examples of acquired cataract-related diseases are senile cataract, secondary cataract, brown cataract, combined cataract, diabetic cataract, and traumatic cataract. Acquired cataract is also induced by electric shock, radiation, ultrasound, drugs, systemic disease, and nutritional disorders. Acquired cataract further includes postoperative cataract.

[0138] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject who has or is suspected of having autosomal dominant optic atrophy (DOA). DOA is a genetic X-linked neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerve. It affects approximately 1 in 10,000 (Denmark) to 1 in 30,000 (worldwide). Nerve damage causes vision loss. It generally begins to appear by age 10 and progresses thereafter. The disease itself primarily affects the retinal ganglion nerves. Mutations in genes known as OPA1 and OPA3, which code for mitochondrial inner membrane proteins (leading to mitochondrial dysfunction), are generally associated with DOA.

[0139] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject having or suspected of having Leber's Hereditary Optic Neuropathy (LHON). LHON is a genetically-based inherited disease that typically begins to manifest between the ages of 15-35. In LHON, mitochondrial mutations affect complex I subunit genes in the respiratory chain that typically result in selective degeneration of retinal ganglion cells (RGCs) and optic nerve atrophy within one year of disease onset. LHON is caused by mutations in the MT-NDI1, MT-ND4, MT-ND4L, and MT-ND6 genes, all of which are associated with the mitochondrial genome encoding. LHOH affects approximately 1 in 50,000 people worldwide. It typically begins in one eye and progresses rapidly to the other eye. Subjects with LHON may eventually become legally or completely blind, often before the age of 50. LHON affects the visual acuity required for tasks such as reading, driving, and recognizing others.

[0140] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject having or suspected of having retinopathy pigmentosa (PR). PR is a frequent feature of retinitis pigmentosa. Retinopathy pigmentosa is a non-specific finding that can be found in several mitochondrial diseases, such as neurogenic anaphylaxis, ataxia, and retinitis pigmentosa (NARP). PR is an inherited degenerative disorder of the retina, characterized by progressive photoreceptor damage. The damage leads to photoreceptor atrophy and cell death. Patients with PR may follow an autosomal dominant, autosomal recessive, or X-linked recessive pattern. The prevalence is about 1 in 3-4 thousand individuals. Symptoms of the disease include night blindness (night blindness), peripheral visual field constriction, and sometimes loss of central vision or visual field.

[0141] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject having or suspected of having retinitis pigmentosa. Retinitis pigmentosa is a disorder characterized by rod and / or cone cell damage. The presence of dark lines in the retina is typical of individuals suffering from retinitis pigmentosa. Individuals with retinitis pigmentosa also exhibit various symptoms, including, but not limited to, headaches, numbness or tingling in the extremities, flashing lights, and / or vision changes. See, e.g., Heckenlively et al., Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol. 105(5):504-511 (1988).

[0142] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject having or suspected of having glaucoma. Glaucoma is a disease characterized by an increase in intraocular pressure, resulting in a decrease in visual acuity. The elevated pressure affects not only the optic nerve, but also the retinal ganglion cells (RGCs) of the retina. Some possible in vitro systems that can be used to evaluate treatments for glaucoma are in vitro RGC-based. Glaucoma can result from various ophthalmological conditions that are already present in an individual, such as wounds, surgery, and other structural anomalies. Glaucoma can occur at any age, but frequently develops in older individuals, leading to blindness. Glaucoma patients typically have an intraocular pressure greater than 21 mmHg. However, normal pressure glaucoma can occur in the absence of such increased intraocular pressure, i.e., pressure greater than 21 mmHg, when glaucomatous changes are found in the visual field and optic nerve head. Symptoms of glaucoma include, but are not limited to, blurred vision, severe eye pain, headache, seeing halos around lights, nausea, and / or vomiting.

[0143] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject who has or is suspected of having ocular hypertension. Intraocular pressure (IOP) above 21 mmHg without optic nerve damage is known as ocular hypertension. Elevated IOP due to inadequate ocular drainage is the main cause of glaucoma.

[0144] In some embodiments of any of the above-mentioned methods, the peptide mimetic is administered to a subject who has or is suspected of having uveitis.Uveitis is a number of intraocular inflammatory diseases of the eye that often lead to irreversible vision loss.Uveitis is the cause of an estimated 30,000 new cases of legal blindness in the United States every year.This disease is believed to be at least partially caused by retinal tissue damage that causes excessive mitochondrial oxidative stress, which induces a damaging immune response.

[0145] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject who has or is suspected of having choroidal neovascularization. Choroidal neovascularization (CNV) is a disease characterized by the development of new blood vessels in the choroid layer of the eye. The newly formed blood vessels grow into the choroid through Bruch's membrane and invade the subretinal space. CNV can lead to impaired vision or complete loss of vision. Symptoms of CNV include, but are not limited to, blinking, flashing, or gray spots visible in the affected eye(s), blurred vision, distorted vision, and / or loss of vision.

[0146] In some embodiments of any of the above methods, the peptidomimetic is administered to a subject who has or is suspected of having retinal degeneration. Retinal degeneration is a disease associated with the degeneration of the retina. Retinal tissue may degenerate for various reasons, such as arterial or venous occlusion, diabetic retinopathy, retinopathy of prematurity, and / or retrolental fibroplasia. Retinal degeneration generally includes retinoschisis, lattice degeneration, and is associated with progressive macular degeneration. Symptoms of retinal degeneration include, but are not limited to, vision impairment, vision loss, night blindness, tunnel vision, peripheral vision loss, retinal detachment, and / or light sensitivity.

[0147] In some embodiments of any of the aforementioned methods, the peptide mimetic is administered to a subject having or suspected of having Stargardt disease, also known as Stargardt macular dystrophy, juvenile macular degeneration, or fundus flava, a rare genetic disease that affects 1 in 8-10 thousand people and causes progressive degeneration of the macula. Stargardt disease typically causes vision loss during childhood or adolescence, but in some forms, vision loss may not be noticed until later in adulthood. Mutations in the ABCA4 gene are the most common cause of Stargardt disease. This gene normally produces a protein that removes vitamin A byproducts in photoreceptors. Cells lacking the ABCA4 protein accumulate clumps of lipofuscin, a fatty substance that forms yellowish spots. As clumps of lipofuscin increase in and around the macula, central vision becomes impaired. Eventually, these fatty deposits lead to the death of photoreceptors and vision becomes further impaired. Other forms of Stargardt disease are associated with mutations in the ELOVL4 gene or the PROM1 gene. Fundus flaviformis (FFM) is an allelic subtype of Stargardt disease that is associated with mutations in the ABCA4 and PRPH2 genes. Stargardt disease is one of the most frequent causes of macular degeneration in childhood. It has an onset between 7 and 12 years, a rapidly progressive course, and ultimately a poor visual outcome. Visual acuity is severely reduced, but peripheral vision remains normal throughout life. Fundus flaviformis is a form of fundus flaviformis, and its name comes from the occurrence of many yellow spots that are distributed rather uniformly across the fundus. In some older patients, the spots disappear over time as atrophy of the retinal pigment epithelium (RPE) increases. Round, linear, or fish-shaped lesions are distributed in the posterior pole, sometimes extending to the equator, with macular involvement. Network atrophy of the retinal pigment epithelium, and choroidal vascular atrophy are characteristic. It is characterized by central vision loss, loss of color vision, photophobia, paracentral scotoma, and slow dark adaptation.

[0148] In some embodiments of any of the aforementioned methods, the peptidomimetic is administered to a subject who has or is suspected of having Kearns-Sayre syndrome. Kearns-Sayre syndrome is a condition that affects many parts of the body, particularly the eyes. Features of Kearns-Sayre syndrome usually appear before the age of 20, and the condition is diagnosed by several characteristic signs and symptoms. People with Kearns-Sayre syndrome have progressive external ophthalmoplegia. Affected individuals also have an eye condition called pigmentary retinopathy, which results from the breakdown (degeneration) of the retina, giving it a spotted and striped appearance.

[0149] In some embodiments of any of the aforementioned methods, the peptide mimetic is administered to a subject with or suspected of having Leber's congenital amaurosis (LCA). LCA comprises a group of early-onset childhood retinal dystrophies characterized by reduced vision, nystagmus, and severe retinal dysfunction. LCA is a progressive autosomal recessive disease that is manifested by loss of photoreceptors, reduced visual fields, and flat electroretinography (ERG) tracings. Most patients become profoundly blind by their teenage years. Patients usually present at birth with severely reduced vision and pendular nystagmus. Electroretinogram (ERG) responses are usually not recordable. Other clinical findings may include hyperopia, photodysphoria, finger signs, keratoconus, cataracts, and variable appearance of the fundus. Different subtypes of LCA have been reported. The different subtypes are caused by mutations in different genes. Some of these subtypes are also distinguished by their patterns of vision loss and associated ocular abnormalities. Treatment includes corrective hyperopia and, when possible, the use of low vision aids. In some forms of LCA, the underlying defect is in the RPE65 gene, which is expressed in RPE cells and codes for an isomerohydrolase involved in the production of 11-cis retinal. Without a functioning RPE65, RPE cells cannot deliver vitamin A to the photoreceptors.

[0150] Prevention methods: Eye diseases are generally progressive, often leading to complete loss of vision, such that it becomes impossible to recognize objects and people. In extreme cases, it can cause total blindness. Sometimes the disease, disorder, or condition progresses slowly, and sometimes more quickly. The administration of a drug that delays the progression of any vision loss (i.e., prevents progression, inhibits progression, improves progression, or delays the onset of certain conditions related to the progression of the disease or disorder) would be highly beneficial to subjects with eye diseases, disorders, or conditions that result in progressive vision loss.

[0151] Thus, administration of the methods or peptidomimetics disclosed above can be considered prophylactic in the sense that they slow the progression of vision loss in a subject.Thus, in one aspect, the present technology provides a method for preventing, inhibiting, ameliorating, or delaying the onset of a subject's ocular disease, disorder, or condition that leads to progressive vision loss by administering to the subject a peptidomimetic, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof.

[0152] Subjects at risk for ocular diseases, disorders, or conditions can be identified, for example, by any one or a combination of diagnostic or prognostic assays. In prophylactic applications, pharmaceutical compounds, compositions, or agents comprising the peptidomimetic, such as the peptidomimetic of formula I, or its pharma- ceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates, are administered to subjects suspected of or otherwise at risk for a disease, disorder, or condition in an amount sufficient to eliminate or reduce the risk of, reduce the severity of, or delay the onset of the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and the pathological phenotypes mediating the disease during its development. Prophylactic administration of the peptidomimetic can occur prior to the appearance of symptoms characteristic of an abnormal condition, thereby preventing the disease or disorder, or alternatively inhibiting, ameliorating, or delaying its progression. Depending on the type of abnormal condition, a peptide mimetic such as a peptide mimetic of formula I, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, acts to enhance or improve mitochondrial function or reduce oxidative damage and can be used to treat a subject. Appropriate compounds can be determined based on screening assays disclosed in the art.

[0153] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with macular degeneration (including, but not limited to, age-related macular degeneration (wet or dry)).

[0154] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with dry eye.

[0155] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with diabetic retinopathy.

[0156] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with diabetic macular edema.

[0157] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with cataracts.

[0158] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with autosomal dominant optic atrophy (DOA).

[0159] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Leber's Hereditary Optic Neuropathy (LHON).

[0160] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Leber's Hereditary Optic Neuropathy (LHON).

[0161] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Leber's Hereditary Optic Neuropathy (LHON).

[0162] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with pigmentary retinopathy.

[0163] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with retinitis pigmentosa.

[0164] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with glaucoma.

[0165] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with ocular hypertension.

[0166] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with uveitis.

[0167] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with chronic progressive external ophthalmoplegia.

[0168] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Kearns-Sayre Syndrome.

[0169] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Leber's congenital amaurosis (LCA).

[0170] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with choroidal neovascularization.

[0171] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with retinal degeneration.

[0172] In some embodiments, a peptidomimetic of Formula I, Formula (II), Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula V, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (or a formulation or medicament comprising the peptidomimetic) is administered to a subject to prevent, inhibit, ameliorate, or delay the onset of vision loss associated with Stargardt's disease.

[0173] Uses, Compositions, Formulations, and Medicaments: The peptidomimetics disclosed herein can be administered in a formulation or medicament (also referred to herein as a composition). Alternatively, a composition generally refers to a mixture that contains a peptidomimetic, but also contains other compounds, such as solvents, or ingredients intended to aid in the preparation of the formulation or medicament. The formulation or medicament can be used in any of the above methods. Typically, the formulation or medicament is specifically prepared for use in the management of the particular disease, disorder, or condition to be addressed.

[0174] In some embodiments, the composition, formulation, or medicament is prepared by dissolving or suspending the peptidomimetic in a diluent, adjuvant, excipient, or vehicle, such as water or a solvent mixture containing water. In some embodiments, the formulation or medicament further comprises a preservative. In some embodiments, the preservative is present in the formulation or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of less than 1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 0.5-1% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 1-2% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 2-3% (weight / volume). In some embodiments, the peptidomimetic(s) is present in the formulation or medicament at a concentration of 3-5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the formulation or medicament at a concentration of greater than 5% (weight / volume). In some embodiments, the peptidomimetic(s) are present in the formulation or medicament at a concentration of greater than 10% (weight / volume).

[0175] Thus, in one aspect, the disclosure provides for the use of a composition in the preparation of a formulation or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of (i) an ocular disease, disorder, or condition, or (ii) deterioration of ellipsoid zone integrity in one or more eyes, in a mammalian subject in need thereof, the composition comprising a therapeutically effective amount of at least one peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. For example, the peptidomimetic can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma-ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0176] In one aspect, the disclosure provides a formulation or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of (i) an ocular disease, disorder condition, or (ii) deterioration of ellipsoid zone integrity in one or more eyes in a mammalian subject in need thereof, the formulation or medicament comprising a therapeutically effective amount of at least one peptidomimetic, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. For example, the peptidomimetic used in the formulation can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (i.e., Formula II), or a pharma-ceutically acceptable salt (e.g., (Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is a peptidomimetic of Formula I, or a pharma-ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof: [ka] During the ceremony, AA 1 teeth, [ka] is selected from AA 2 teeth, [ka] is selected from R 1 teeth, [ka] is selected from R 2a teeth, [ka] is selected from R2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is [ka] is selected from * is X R 1 wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

[0177] Determining the biological effects of peptidomimetic-based therapeutics In various embodiments, suitable in vitro or in vivo assays can be performed to determine the effect of a particular peptidomimetic-based therapeutic and whether its administration is indicated for treatment or prevention. In various embodiments, in vitro assays can be performed on cells representative of the type(s) involved in the disorder of interest to determine whether a given peptidomimetic-based therapeutic exerts the desired effect on the cell type(s). Compounds for use in therapy or prevention can be tested in suitable animal model systems. Similarly, for in vivo testing, any of the animal model systems known in the art can be used prior to administration to human subjects. In one embodiment, administration of a peptidomimetic of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or a pharma- ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof to a subject exhibiting symptoms associated with an ocular condition will cause an improvement in (or prevention, inhibition, amelioration, delay in the onset of) one or more of the diseases, disorders, or conditions experienced by the subject.

[0178] The effect of a peptidomimetic-based therapeutic agent on an ocular disease, disorder, or condition in a subject can be determined by examination of one or more eyes of the subject. In some embodiments, such a determination can be made using an examination technique, such as, for example, measuring the subject's best corrected visual acuity (BCVA) over time to determine whether the subject's vision is stable, improving, or worsening. In some embodiments, such a determination can be made using an examination technique, such as, for example, measuring the subject's low light visual acuity (LLVA) over time to determine whether the subject's vision is stable, improving, or worsening. In some embodiments, such a determination can be made using an examination technique that involves the use of any of the various forms of optical coherence tomography (OCT, including SDOCT, (TD)OCT, or SS-OCT, or OCTA) of the subject over time to determine whether the subject's vision is stable, improving, or worsening. In some embodiments, these examinations are used to evaluate the structure of the external limiting membrane (ELM), Bruch's membrane (BM), ellipsoid zone (EZ), interdigitation zone (IZ), and retinal pigment epithelium (RPE). Use of this technology, particularly various forms of OCT, can access EZ integrity and EZ-RPE changes, and any deterioration thereof over time. In some embodiments, administration of a peptidomimetic of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or a pharma- ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof to a subject exhibiting symptoms associated with an ocular condition will, in some cases, result in an improvement in (or prevention, inhibition, amelioration, delay in the onset of) one or more of the diseases, disorders, or conditions experienced by the subject, including deterioration of ellipsoid zone integrity in the subject.

[0179] The data shown in Examples 1, 3, and 4 demonstrate that the compound of formula II (specifically, the salt form of formula IIa) accumulates in the eye (including the substructures of the eye) in amounts expected to be therapeutically effective. The data in Example 1 show that the compound of formula IIa accumulates in rabbit eyes (and their substructures) at higher concentrations than elamipretide (whether administered topically or subcutaneously), a compound that has been shown to be therapeutically active in recent P1 and P2 human clinical trials, including correlations related to improved LLVA in conjunction with improved EZ integrity (see introduction above). Both elamipretide and the peptide mimetic of formula I target mitochondria. Example 2 demonstrates that both elamipretide and the compound of formula IIa show similar beneficial effects of improving mitochondrial function in RPE cells derived from AMD donors. For these reasons, the peptidomimetics (e.g., of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or pharma- ceutically acceptable salts thereof) are expected to be useful in treating, preventing, inhibiting, ameliorating, or delaying the onset of ocular diseases, disorders, and conditions, including, but not limited to, GA, glaucoma, and / or wet or dry age-related macular degeneration. Furthermore, based on these results, administration of the peptidomimetics (e.g., of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or pharma-ceutically acceptable salts thereof) is expected to be useful in treating, preventing, inhibiting, ameliorating, or delaying the onset of deterioration of (mitochondria-rich) ellipsoid zone health in one or more eyes of a mammalian subject in need thereof.

[0180] Animal models: Compounds for use in therapy can be tested in suitable animal model systems, including but not limited to rats, mice, chickens, cows, monkeys, rabbits, etc., prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model systems known in the art can be used prior to administration to human subjects. In some embodiments, in vitro or in vivo testing is directed to the biological function of the compound of formula (II), or a pharma- ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the in vitro or in vivo testing is directed to the biological function of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., (IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the animal model is a Sprague Dawley rat.

[0181] Mode of Administration and Effective Dosage: Any method known to one of skill in the art for contacting a cell, organ, or tissue with a peptidomimetic of formula (I), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the cell, organ, or tissue is contacted with (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (formula II), or a pharma- ceutically acceptable salt (e.g., (formula IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof. Suitable methods include in vitro, ex vivo, or in vivo methods. In vivo methods typically include administering the peptidomimetic to a mammal, such as a human. When used in vivo for therapy, a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof can be used. Dosage and administration regimens will depend on the extent of the disease, disorder, or condition in the subject, the characteristics of the particular peptidomimetic used, e.g., its therapeutic index, the subject, and the subject's medical history.

[0182] Effective amounts can be determined during preclinical and clinical trials by methods familiar to physicians and clinicians. An effective amount of a peptidomimetic useful in the present methods can be administered to a mammal in need thereof by any of several well-known methods for administering pharmaceutical compounds. For example, the peptidomimetic can be administered subcutaneously, intravitreally, topically, intraocularly, ocularly, orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

[0183] Peptide mimetics may be formulated as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to a patient, such as a mammal (e.g., salts that have acceptable mammalian safety for a given dosing regimen). However, it should be understood that salts, such as salts of intermediate compounds that are not intended for administration to a patient, do not have to be pharmaceutically acceptable salts. Pharmaceutically acceptable salts may be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. In addition, when a peptide or peptidomimetic contains both a basic moiety, such as an amine, pyridine, or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term "salt" as used herein. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharma- ceutically acceptable organic bases include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, trimethylamine (NEt 3 ), trimethylamine, tripropylamine, tromethamine, and other organic bases in their protonated form (e.g., [HNEt 3 ] +), including salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc. Salts derived from pharma-ceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (hydrobromic, hydrochloric, hydrofluoric, or hydroiodic acids), nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid. Salts derived from pharma- ceutically acceptable organic acids include salts derived from aliphatic hydroxyl acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid, and triphenylacetic acid), aromatic hydroxyl acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene acid, 1-hydroxyphenylacetic ... Examples of suitable carboxylic acids include naphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid, ascorbic acid, dicarboxylic acids (e.g., fumaric, maleic, oxalic, and succinic acids), glucuronic acid, mandelic acid, mucilaginous, nicotinic acid, orotic acid, pamoic acid, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, edisylic acid, ethanesulfonic acid, isethionic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, and p-toluenesulfonic acid (PTSA)), and xinafoic acid.In some embodiments, the pharma- ceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. In some embodiments, the salt is a tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case a mono-, bis- or tri-(tris-) acid salt), monoacetate, bis-acetate, tri-acetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, monohydrochloride, bis-hydrochloride, tri-(tris-) hydrochloride (e.g., Formula IIa), mono-tosylate, bis-tosylate, or tri-tosylate. In some embodiments, the peptidomimetic is formulated as a mono-HCl, bis-HCl, or tri-(or tris)HCl salt (e.g., Formula IIa).

[0184] A peptidomimetic described herein, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, can be incorporated into a pharmaceutical composition (e.g., formulation or medicament) for administration alone or in combination to a subject for the treatment or prevention of a disease, disorder, or condition described herein. The peptidomimetic can be formulated with other compounds, such as a therapeutic agent, a peptide, another peptidomimetic, or mixtures thereof. In some embodiments of the method of the present technology, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. Such pharmaceutical compositions typically include an active agent and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can be used as a medicament or in the preparation of a medicament for administration to a subject suffering from an ophthalmic condition or disease. The pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.

[0185] A pharmaceutical composition (e.g., a formulation or medicament) can be formulated to be compatible with its intended route of administration. Exemplary routes of administration include parenteral (e.g., intravenous, intradermal, intraperitoneal, or subcutaneous), oral, systemic, intravitreal, inhalation, transdermal (topical), intraocular, ocular, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, and intramuscular administration. In some embodiments, the route of administration is oral. In some embodiments, the route of administration is subcutaneous. In some embodiments, the route of administration is topical. In some embodiments, the route of administration is intraocular. In some embodiments, the route of administration is ocular.

[0186] Solutions or suspensions (e.g., formulations or medicaments) used for parenteral, intradermal, subcutaneous, or intraocular application can contain the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. For the convenience of the patient or treating physician, the formulation to be administered can be provided alone or in a kit containing all the supplies (e.g., vials of drug, vials of diluent, syringes, and needles) needed during a course of treatment (e.g., 7 days or more of treatment).

[0187] Pharmaceutical compositions (e.g., formulations or medicaments) suitable for injectable use can include sterile aqueous solutions (if water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). Compositions for administration by injection generally must be sterile and fluid to the extent that they are easily syringable. They must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0188] The peptidomimetic-containing composition (e.g., formulation or agent) may contain a carrier, which may be a solvent or dispersion medium, including, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerazole, and the like. Glutathione and other antioxidants may be included to prevent oxidation. In many cases, it is advantageous to include an isotonic agent, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of an injectable composition may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0189] Sterile injectable solutions (e.g., formulations or medicaments) can be prepared by incorporating the required amount of active compound into a suitable solvent containing one or a combination of the above-listed ingredients as needed, followed by filtration sterilization.In general, dispersions are prepared by incorporating active compound into a sterile vehicle containing a basic dispersion medium and other ingredients required from those listed above.In the case of sterile powders for preparing sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, which can obtain a powder of active ingredient plus any additional desired ingredients from the solution previously sterile-filtered.

[0190] Oral compositions (e.g., formulations or medicaments) will generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, such as gelatin capsules. Oral compositions can also be prepared using fluid carriers for use as mouthwashes. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches, and the like can contain any of the following ingredients: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel®, or corn starch; lubricants such as magnesium stearate or sterates; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature.

[0191] The volume of the formulation or medicament containing the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof with an inert material may be diluted or increased. These diluents may include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts, including calcium triphosphate, magnesium carbonate, and sodium chloride, may also be used as bulking agents. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress®, and Avicel®.

[0192] Disintegrants may be included in formulations or medicaments that contain compounds, therapeutic agents, peptides, peptidomimetics, or mixtures thereof in solid dosage form with inactive substances. Materials used as disintegrants include, but are not limited to, commercially available disintegrants based on starch, such as starch, including Explotab®. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge, and bentonite may all be used as disintegrants. Another form of disintegrant is the insoluble cation exchange resin. Powdered gums may be used as disintegrants and binders, and these may include powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0193] Binders are used to hold the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof in the formulation with inert materials to form a hard tablet, and may include materials derived from natural products such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the formulation.

[0194] Antifriction agents may be included in the formulation or drug containing the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof to prevent adhesion during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the wall of the die, and may include, but are not limited to, stearic acid, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes, including magnesium and calcium salts. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000 may also be used.

[0195] Glidants may be added during formulation to improve the flow properties of the drug and aid in rearrangement during compression. Glidants may include starch, talc, fumed silica, pyrogenic silica, and hydrated silicoaluminate.

[0196] Surfactants may be added as wetting agents to help dissolve the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof in an aqueous environment. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used and may include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation or medicament containing the compound, therapeutic agent, peptide, peptidomimetic, or mixture or derivative thereof of this technology either alone or as a mixture in different ratios.

[0197] Pharmaceutical preparations (formulations or medicaments) that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Microspheres formulated for oral administration can also be used. Such microparticles are well defined in the art. All formulations or medicaments for oral administration should be in dosages suitable for such administration.

[0198] For administration of the formulation, agent, or compound by inhalation for use according to the present application, it can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, the formulation, agent, or compound can be delivered in the form of an aerosol spray from a pressurized container or dispenser or nebulizer containing a suitable propellant, for example, a gas such as carbon dioxide. Such methods include those described in U.S. Pat. No. 6,468,798. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0199] A compound, composition (e.g., formulation or drug), therapeutic agent, peptide, peptidomimetic, or mixtures thereof can be delivered to the lungs of a mammal during inhalation and cross the lung epithelial lining into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569(1990); Adjei et al., Int J Pharmaceutics 63:135-144(1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.5):143-146(1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212(1989) (antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery. II, Keystone, Colorado, March, (recombinant human growth hormone), Debs et al., 1988, J Immunol 140:3482-3488 (interferon gamma and tumor necrosis factor alpha) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor, incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al., incorporated by reference.

[0200] Contemplated for use in the practice of the present technology are a wide range of devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those of skill in the art.

[0201] Some specific examples of commercially available devices suitable for the practice of the present technology are the Ultravent™ nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo., the Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo., the Ventolin metered dose inhaler manufactured by Glaxo, Inc., Research Triangle Park, North Carolina, and the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0202] Ophthalmic or intraocular formulations can use any suitable mode of delivery of a peptidomimetic, such as a peptidomimetic of Formula I, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof (with or without a therapeutic agent, peptide, or other peptidomimetic), to the eye or an area near the eye. For example, the peptidomimetic can be (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. For ophthalmic formulations see generally Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, NY (1993) and also Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of formulations suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels. In one embodiment, a contact lens is coated with a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, a single dose comprises 0.1 ng to 5000 μg, 1 ng to 500 μg, or 10 ng to 100 μg of the peptidomimetic administered to the eye.

[0203] Eye drops can include sterile liquid formulations that can be administered directly to the eye. In some embodiments, eye drops can be used that include one or more peptidomimetics described herein, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt thereof (e.g., Formula IIa), stereoisomers, tautomers, hydrates, and / or solvates, and may further include one or more preservatives. In some embodiments, the optimal pH of the eye drops is equal to the pH of tears, which is about 7.4.

[0204] In-situ gels are viscous liquids that exhibit the ability to transition from sol to gel when influenced by external factors such as appropriate pH, temperature, and the presence of electrolytes. This property slows drug efflux from the ocular surface and increases the bioavailability of the active ingredient. Polymers commonly used in in-situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicon-containing formulations, and cellulose acetate phthalate. In some embodiments, compounds, therapeutic agents, peptides, peptidomimetics, or mixtures thereof are formulated into in-situ gels (as pharmaceutical compositions).

[0205] For local ocular administration, the compounds, therapeutic agents, peptides, peptidomimetics, or mixtures thereof may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Ointments are semi-solid dosage forms for external use, such as topical use on the eye or skin. In some embodiments, ointments include solid or semi-solid hydrocarbon bases with melting or softening points close to the core temperature of the human body. In some embodiments, ointments applied to the eye break down into small droplets, which remain in the conjunctival sac for a longer period of time, thus increasing bioavailability.

[0206] Ophthalmic inserts are solid or semi-solid dosage forms that do not have the disadvantages of conventional ophthalmic drug forms. They are less susceptible to defense mechanisms such as outflow through the nasolacrimal duct, exhibit the ability to remain in the conjunctival sac for extended periods, and are more stable than conventional dosage forms. They also offer advantages such as precise dosing of one or more peptidomimetics, slow release of one or more peptidomimetics at a constant rate, and limited systemic absorption of one or more peptidomimetics. In some embodiments, the ophthalmic insert comprises one or more peptidomimetics described herein, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, and one or more polymeric materials. The polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropylmethylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethylchitosan, gelatin, and various mixtures of the aforementioned polymers.

[0207] Minitablets are biodegradable solid dosage forms that migrate into a gel after application to the conjunctival sac, thereby extending the contact period between the active ingredient and the ocular surface, and subsequently increasing the bioavailability of the active ingredient. The advantages of minitablets include easy application to the conjunctival sac, resistance to defense mechanisms such as tears or runoff through the nasolacrimal duct, longer contact with the cornea caused by the presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation at the application site due to swelling of the outer carrier layer. The minitablets can include one or more peptidomimetics described herein, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, and one or more polymers. Non-limiting examples of polymers suitable for use in minitablet formulations include, for example, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose, ethylcellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), carbopol or carbomer, chitosan, and starch (e.g., drum-dried waxy corn starch). In some embodiments, the minitablets further comprise one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0208] Ophthalmic or intraocular preparations may contain antimicrobial components that are non-harmful during use, e.g., non-toxic auxiliary substances such as thimerosal, benzalkonium chloride, methyl and propylparabens, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffer components such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffer; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediaminetetraacetic acid, etc.

[0209] In some embodiments, the viscosity of an ophthalmic formulation comprising one or more peptidomimetics described herein, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, is increased to improve corneal contact and intraocular bioavailability. Viscosity can be increased by adding high molecular weight hydrophilic polymers that do not diffuse through biological membranes and form three-dimensional networks in water. Non-limiting examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, as well as polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0210] Systemic administration of the compounds, compositions (e.g., formulations or drugs), therapeutic agents, peptides, peptidomimetics, or mixtures thereof described herein may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays. For transdermal administration, the active compounds are generally formulated into ointments, salves, gels, or creams, as known in the art. In one embodiment, transdermal administration may be performed by iontophoresis.

[0211] The compound, composition (e.g., formulation or drug), therapeutic agent, peptide, peptidomimetic, or mixture thereof can be formulated in a carrier system. The carrier can be a colloidal system. The colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, the compound, composition (e.g., formulation), therapeutic agent, peptide, peptidomimetic, or mixture thereof is encapsulated in a liposome while maintaining the integrity of the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof. Those skilled in the art will understand that there are various methods for preparing liposomes. (See Lichtenberg, et al., Methods Biochem. Anal., 33:337-462 (1988); Anselem, et al., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (see Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). For example, active agents can also be loaded into particles prepared from pharma- ceutically acceptable components, including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable, or digestion-promoting polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0212] The carrier can also be a polymer, for example, a biodegradable, biocompatible polymer matrix. In one embodiment, the compound, composition (e.g., formulation), therapeutic agent, peptide, peptidomimetic, or mixtures thereof can be embedded in the polymer matrix while maintaining the integrity of the composition. The polymer can be natural, such as a polypeptide, protein, or polysaccharide, or synthetic, such as poly-alpha-hydroxy acid. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or copolylactic / glycolic acid (PLGA). The polymer matrix can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. The polymer formulation can provide an extended duration of therapeutic effect. (See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). Polymer formulations for human growth hormone (hGH) have been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0213] Examples of polymeric microsphere sustained release formulations are described in PCT Publication No. 99 / 15154 (Tracy et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (both Zale et al.), PCT Publication No. 96 / 40073 (Zale et al.), and PCT Publication No. 00 / 38651 (Shah et al.). U.S. Patent Nos. 5,674,534 and 5,716,644, and PCT Publication No. 96 / 40073, describe polymer matrices containing particles of erythropoietin stabilized against aggregation with salts.

[0214] In some embodiments, therapeutic compounds are prepared with carriers that protect the compounds, compositions (e.g., formulations), therapeutic agents, peptides, peptidomimetics, or mixtures thereof from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Such formulations can be prepared using known techniques. Materials can also be obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to specific cells with monoclonal antibodies against cell-specific antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0215] Therapeutic compounds can also be formulated to enhance intracellular delivery. For example, liposome delivery systems are known in the art, see, for example, Chonn and Cullis, "Recent Advances in Liposome Drug Delivery Systems," Current Opinion in Biotechnology 6:698-708 (1995); Weiner, "Liposomes for Protein Delivery: Selecting Manufacturing and Development Processes," Immunomethods, 4(3):201-9 (1994); and Gregoriadis, "Engineering Liposomes for Drug Delivery: Progress and Problems," Trends Biotechnol., 13(12):527-37 (1995). Mizguchi, et al., Cancer Lett., 100:63-69 (1996) describe the use of fusogenic liposomes to deliver proteins to cells both in vivo and in vitro.

[0216] In addition to the above formulations, the compounds, compositions, therapeutic agents, peptides, peptidomimetics, or mixtures thereof can also be formulated as depot preparations. Such long-acting preparations can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0217] The compound, composition, therapeutic agent, peptide, peptidomimetic, or mixture thereof may be provided in a particle or polymer microsphere. Examples of polymer microsphere sustained release formulations are described in PCT Publication No. 99 / 15154 (Tracy et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (both Zale et al.), PCT Publication No. 96 / 40073 (Zale et al.), and PCT Publication No. 00 / 38651 (Shah et al.). U.S. Patent Nos. 5,674,534 and 5,716,644, and PCT Publication No. 96 / 40073, describe a polymer matrix that includes particles of erythropoietin stabilized against aggregation with salt. The particle may include a therapeutic agent(s) within a core surrounded by a coating, including but not limited to an enteric coating. The compound, composition, therapeutic agent, peptide, peptidomimetic, or mixture thereof may also be dispersed throughout the particle. The compound, composition, therapeutic agent, peptide, peptidomimetic, or mixture thereof may also be adsorbed into the particle. The particle may have any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the compound, composition, therapeutic agent, peptide, peptidomimetic, or mixture thereof, the particle may contain any of those materials conventionally used in the pharmaceutical and medical fields, including, but not limited to, erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof. The particle may be a microcapsule containing the compound of the present technology in solution or in a semi-solid state. The particle may be of virtually any shape.

[0218] Both non-biodegradable and biodegradable polymeric materials may be used in the manufacture of particles for delivering compounds, compositions, therapeutic agents, peptides, peptidomimetics, or mixtures thereof. Such polymers may be natural or synthetic polymers. The polymers may be natural, such as polypeptides, proteins, or polysaccharides, or synthetic, such as poly-alpha-hydroxy acids. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin, and combinations thereof. Bioadhesive polymers of particular interest include the bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginates, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), and polycaprolactone.

[0219] The compound, composition, therapeutic agent, peptide, peptidomimetic, or mixtures thereof may be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. It refers to immediate and non-immediate release formulations, including, but not limited to, sustained and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of drug over an extended period of time, preferably, but not necessarily, resulting in a substantially constant blood level of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a delay in time between administration of the formulation and the release of drug therefrom. "Delayed release" may or may not involve a gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release".

[0220] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic diseases. "Long-term" release, as used herein, means that the implant (depot) is constructed and arranged to deliver therapeutic levels of the active ingredient (i.e., compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof) for at least 7 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 180 days, or at least 365 days. In some embodiments, "long-term" release means 30-60 days, 60-90 days, 90-120 days, 120-180 days, or 180-365 days. Long-term sustained release implants are well known to those of skill in the art and include some of the release systems described above.

[0221] The dosage, toxicity and therapeutic efficacy of any compound, composition (e.g., formulation), therapeutic agent, peptide, peptidomimetic or mixture thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. Compounds that exhibit toxic side effects may be used, but care must be taken to design a delivery system that targets such compounds to the site of the affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0222] Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds can be 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 employed and the route of administration utilized. For any compound used in the method, a therapeutically effective dose can be estimated initially from cell culture assays. Doses 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 of symptoms) determined in cell culture. Such information can be used to accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0223] Typically, an effective amount of the peptidomimetic sufficient to achieve a therapeutic or prophylactic effect ranges from about 0.000001 mg per kilogram of body weight per day to about 10,000 mg per kilogram of body weight per day. Suitably, the dose range is from about 0.0001 mg per kilogram of body weight per day to about 100 mg per kilogram of body weight per day. For example, dosages can be in the range of 0.5-1 mg / kg body weight or 1-10 mg / kg body weight daily, every 2 or 3 days, or 1-10 mg / kg every week, every 2 or 3 weeks. In one embodiment, a single dosage of the peptide or peptidomimetic ranges from 0.001 to 10,000 micrograms per kg of body weight. In one embodiment, the concentration of the mitochondrial targeted peptidomimetic in the carrier ranges from 0.2 to 2000 micrograms per milliliter delivered. An exemplary treatment regime involves administration once a day or once a week. In therapeutic applications, relatively high dosages at relatively short intervals may be required until the progression of the disease is reduced or terminated, or until the subject shows partial or complete improvement of the symptoms of the disease. Thereafter, the patient may be administered a prophylactic regimen.

[0224] In some embodiments, a therapeutically effective amount of a peptidomimetic is 10 -12 ~10 -6 Molar, e.g., about 10 -7 The therapeutic concentration may be defined as the concentration of the peptidomimetic in a target tissue in millimolar doses. This concentration may be delivered by a systemic dose of 0.001-100 mg / kg or equivalent by body surface area. The dosing schedule will be optimized to maintain a therapeutic concentration in the target tissue, such as by a single daily or weekly administration, but also includes continuous administration (e.g., parenteral injection or transdermal application).

[0225] One of ordinary skill in the art will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof described herein can include a single treatment or a series of treatments.

[0226] Combination therapy: In some embodiments, a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, may be combined with one or more additional therapeutic agents for the prevention or treatment of an ocular condition or disease. In some embodiments of the methods of the present technology, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof.In some embodiments, the additional therapeutic agent is carbatiol (Carbastat® or Carboptic®), polocarpine (Salagen®), timolol (Timoptic®), betaxolol (Betoptic® or Keflone®), carteolol (Cartrol® or Ocupress®), levobunolol (Liquifilm®), brimonidine (Lumify® or Mirvaso®), apraclonidine (Iopidine®), latanoprost (Xalantan®), travoprost (Travatan®), or cefotaxime (Citrolev®). trademark), bimatoprost (Lumigan®), talfluprost (Taflotan®), unoprostone isopropyl (Rescula®), dorzolamide (Trusopt®), brinzolamide (Azopt®), acetazolamide (Diamox®), methazolamide (Neptazane®), brimonidine tartrate / timolol maleate (Combigan®), timolodorzolamide (Cosopt®), travoprost-timolol (DuoTrav®), and latanoprost and timolol maleate (Xalacom®).

[0227] In some embodiments, a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, may be combined (alone or in a formulation) with one or more additional therapeutic agents selected from antioxidants, metal complexing agents, anti-inflammatory agents, antibiotics, and antihistamines. In some embodiments, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, alpha-lipoic acid, coenzyme Q, glutathione, or a carotenoid.In some embodiments, the additional therapeutic agent is aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demeclovir, tetracycline ... Potassium, dexamethasone, diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurane, ketorolac, ketotif cephalosporin, latanoprost, levobetaxolol, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, progesterone, Selected from the group consisting of loparacaine, ranibizumab, rimexolone, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinuron, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarubine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations of two or more of the foregoing.

[0228] In some embodiments, any one of the aforementioned additional therapeutic agents is administered separately, simultaneously, or sequentially with the mitochondrial targeted peptidomimetic(s). In some embodiments, the dose of the additional therapeutic agent is about 0.5 mg / kg to about 2 mg / kg, about 1 mg / kg to about 2 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 75 mg / kg, or about 25 mg / kg to about 50 mg / kg. In some embodiments, the dose of resveratrol is 0.8 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 75 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 175 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, or more. In some embodiments, the additional therapeutic agent is administered twice a day, daily, every 48 hours, every 72 hours, twice a week, once a week, once every two weeks, once a month, once every two months, once every three months, or once every six months. In some embodiments, the dose of the additional therapeutic agent depends on the weight and / or age of the subject.

[0229] In one embodiment, the additional therapeutic agent is administered to the subject in combination with at least one peptidomimetic to produce a synergistic therapeutic effect.For example, the administration of at least one peptidomimetic with one or more additional therapeutic agents for the prevention or treatment of ocular conditions or diseases will have a greater than additive effect in the prevention or treatment of the condition or disease.Therefore, a lower dose of any one or more of the individual therapeutic agents can be used in treating or preventing ocular conditions or diseases, resulting in increased therapeutic efficacy and reduced side effects.

[0230] In some embodiments, the multiple therapeutic agents can be administered in any order, or even simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents can be given in multiple doses, or both can be given as multiple doses. If not simultaneously, the timing between multiple administrations can vary from more than 0 weeks to less than 4 weeks. In addition, the combination methods, compositions, and formulations are not limited to the use of only two agents.

[0231] In some embodiments, a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., (Formula IIa)), stereoisomer, tautomer, hydrate, and / or solvate thereof, may be combined with one or more additional therapeutic techniques, including, for example, gene therapy for the prevention or treatment of a disease, such as a monogenic disorder of the eye. Thus, in some embodiments, a peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharma- ceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, may be administered to a subject in combination with gene therapy. EXAMPLES

[0232] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way. Example 1 - Comparison of the uptake of elamipretide and the compound of formula IIa in plasma and various compartments of the eye in a rabbit model A. Test item: (i) Elamipretide (ii) A compound of formula IIa B. Formulations in the various groups tested: (i) Groups 1 and 3: Subcutaneous administration of elamipretide (corrected for potency) or compound of formula IIa

[0233] Elamipretide or compound of formula IIa at 3 mg / mL in saline was administered subcutaneously at 1.5 mg / kg. Elamipretide or compound of formula IIa formulation at 3 mg / mL was prepared by dissolving 81 mg of elamipretide in a total volume of 27 mL of sterile saline and mixing thoroughly. (ii) Groups 2 and 4: Topical ophthalmic formulations for administration of elamipretide or a compound of formula IIa

[0234] For each preparation (i.e., elamipretide or compound of formula IIa), sodium chloride (105 mg) was dissolved in 16 mL of water for injection with mixing. Then, 82.8 mg of sodium phosphate monobasic monohydrate was added with mixing. 0.400 mL of a 5 mg / mL aqueous solution of benzalkonium chloride (prepared by diluting 0.100 mL of a 50% solution of benzalkonium chloride in water to 10 mL with water for injection) was then added with mixing. Next, two hundred (200) mg of elamipretide or compound of formula IIa was added with mixing and the formulation pH was adjusted to 5.8 (+ / - 0.1) with 1 M sodium hydroxide in water solution. The final volume of the formulation was then made up to 20 mL using water for injection. Each formulation (elamipretide or compound of formula IIa) was used for topical ocular administration at a dose of 50 μL / eye OU.

[0235] In all cases, the formulations were administered on the day of their preparation.

[0236] C. Animals and numbers of animals: A total of 48 male Dutch Belted rabbits were used in the study, each animal weighing approximately 2 kg.

[0237] D. Husbandry: Animals were housed individually in accordance with all applicable laws, regulations, and guidelines. No other species were maintained in the same room. Animals were exposed to a 12-h light / 12-h dark light cycle, except during the dark cycle period when the lights were on to perform any study-related activities. Room temperature was maintained between 16 and 22 °C, and relative humidity was maintained between 30 and 70%.

[0238] All animals had access to rabbit chow on an ad libitum basis. Water was available ad libitum to each animal via a water bottle equipped with a sipper tube. Animals were acclimated to their housing for at least 5 days after receipt at the facility prior to the first day of dosing.

[0239] E. Pre-Study Health and Care of Animals: Prior to shipping, both eyes of all test animals were inspected by the vendor to ensure there were no ocular abnormalities or defects. All animals received for this study were evaluated for their general health. During the acclimation period, each animal was observed for the development of abnormalities or infections.

[0240] All animals were treated according to study protocols, procedures approved by the Institutional Animal Care and Use Committee (IACUC) and comply with acceptable standards of animal welfare and humane care. [Table 1]

[0241] G. Test Article Administration / Medication: For subcutaneous dosing, rabbits were dosed via a single subcutaneous injection of 1.5 mg / kg in the nape of the neck between the shoulder blades using a syringe fitted with a 27 g x 1 / 2 inch needle (or similar). The injection site was checked immediately after administration to ensure no dose was leaked.

[0242] For topical administration, 50 μL of formulation was administered onto the globe using a calibrated Gilson volumetric pipette while the lower eyelid was pulled away from the globe. Dosing was twice daily (i.e., BID). Doses were administered every 8-12 hours to both eyes for a total of 11 doses.

[0243] H. Termination Procedure: Animals were euthanized by barbiturate overdose at designated time points or when necessary for humane reasons.

[0244] Terminal blood samples (approximately 6 mL) were collected from two animals / group / time point via the central ear artery at approximately 0.5, 1, 2, 4, 8, and 24 hours post-dose. Blood samples were diluted with K 2 Blood was collected into tubes containing EDTA, inverted several times to ensure adequate mixing of the blood and anticoagulant, and placed on ice. Within 30 minutes of collection, samples were centrifuged to harvest plasma, which was stored at -80°C until analysis.

[0245] After blood collection, designated animals were euthanized by barbiturate overdose. After euthanasia, both eyes of each rabbit were harvested and dissected for collection of ocular tissues and fluids. Optic nerves and retinas were collected from animals in groups 1 and 3, while aqueous humor, retina, conjunctiva, cornea, sclera, and optic nerves were collected from animals in groups 2 and 4. After dissection, all fluids and tissues were placed into pre-weighed tubes, weights were collected, and then flash frozen on dry ice and placed in a freezer at -80°C or below until analysis. Concentrations of test articles in plasma, ocular tissues (ng / g tissue), and fluids (ng / mL fluid) were determined using methods previously developed by CRO.

[0246] I. Results: The results are shown graphically in Figures 1A-7. With reference to Figures 1A and 1B, the concentrations of elamipretide and the compound of formula IIa in plasma are approximately equivalent, regardless of the mode of administration. However, with reference to Figures 2A and 2B, the concentration of elamipretide accumulated in the retina is much lower than that of the compound of formula IIa, regardless of the mode of administration (i.e., topical or subcutaneous). With reference to Figures 3-7 (all of which are for topical administration only), in all cases, except for the sclera (Figure 6), the concentration of the compound of formula IIa is higher than that of elamipretide in the examined ocular tissues.

[0247] J. Abstract: The data show that the compound of formula IIa accumulates in rabbit plasma at generally similar concentrations compared to elamipretide, whether administered topically or by subcutaneous injection. However, in various ocular tissues (e.g., retina, conjunctiva, cornea, aqueous humor, and optic nerve head), the compound of formula IIa accumulates to higher concentrations than elamipretide, whether administered subcutaneously or topically (i.e., via eye drops).

[0248] Example 2 - Efficacy of Elamipretide and the Compound of Formula IIa in an iPSC-Derived RPE Preclinical Model of Dry AMD Introduction: Age-related macular degeneration (AMD) is characterized by changes in Bruch's membrane followed by dysfunction and atrophy of retinal pigment epithelium (RPE) cells, a key feature of AMD pathogenesis. Somatic cells taken from AMD patients can be reprogrammed to form RPE to model patient-specific disease. This example combines the use of an in vitro model of age-related changes to Bruch's membrane with induced pluripotent stem cell (iPSC)-derived RPE cells from patients with AMD (described in Gong et al. STEM CELLS Transl Med. 9:364-376 (2020) and briefly described below) to demonstrate the efficacy of elamipretide and the compound of formula IIa in methods for treating, preventing, inhibiting, ameliorating, or delaying the onset of dry AMD.

[0249] method: General. iPSC-derived RPE were generated from AMD patients (2 atrophic, 1 exudative) and patients with no history of AMD (n=3). To test the therapeutic efficacy of elamipretide and the compound of formula IIa, cell viability was analyzed for 24 hours in nitrite-modified extracellular matrix (ECM), a typical modification of aging Bruch's membrane. DNA microarrays were used to elucidate gene expression in AMD-derived RPE cultured in nitrite-modified ECM.

[0250] Primary fibroblast culture. Fibroblasts from AMD patients and patients with no history of AMD were isolated as described in Fields et al., PLoS One 12:e0177763 (2017). Details on the patients are provided in Table 2. Cultures were obtained in Dulbecco's modified Eagle's medium (DMEM, Thermo Fisher Scientific, Waltham, MA) containing 10% fetal bovine serum (FBS, Thermo Fisher Scientific) and maintained at 37 °C, 5% CO in a humidified room temperature. 2 The cells were cultured in an incubator. [Table 2]

[0251] Feeder-free and non-integrated reprogramming. 5 × 10 fibroblasts 4Cells were expanded to 1000 cells / well and then treated with modified messenger ribonucleic acid (mRNA) encoding the reprogramming factors octamer-binding transcription factor 3,4 (Oct3 / 4), SRY (sex determining region Y)-box2 (Sox2), Krüppel-like factor 4 (Klf4), c-Myc, NANOG homeobox protein (NANOG), and Lin-28 homolog A (Lin-28) using the fully automated platform New York Stem Cell Foundation (NYSCF) Research Institute Global Stem Cell Array as described in Paull et al., Nat Methods 12:885-892 (2015) or using the Stemgent StemRNA 3rd Gen Reprogramming Kit (REPROCELL USA Inc., Beltsville, MD, www.reprocell.com) according to the manufacturer's protocol. iPSC cultures were expanded by passaging every 5–7 days using Accutase (Sigma-Aldrich, St. Louis, MO, www.sigmaaldrich.com) and cultured for use in downstream experiments.

[0252] Immunofluorescence. After differentiation, iPSC-derived RPE cell lines were fixed and stained as described in Fields et al. (2017). Exemplary antibodies are provided in Table 3. Cell nuclei were labeled with 4',6-diamidino-2-phenylindole (DAPI, Sigma-Aldrich). Cells were visualized by Zeiss LSM800 confocal laser scanning microscope using Zen microscope software (Carl Zeiss, Oberkochen, Germany, www.zeiss.com). [Table 3] iPSC: induced pluripotent stem cell, RPE: retinal pigment epithelium, OCT4: octamer-binding transcription factor 4, Sox2: SRY (sex determining region Y)-box2, SSEA-4: stage-specific embryonic antigen 4, TRA-1-60: keratin sulfate-related antigen-1-60, ZO-1: zonula occludens-1, Na-K ATPase: sodium potassium ATPase, RPE65: retinal pigment epithelium-specific 65 kDa protein.

[0253] Differentiation of human iPSCs into RPE cells. Human iPSC-derived RPE cell lines were differentiated as described in Fields et al. (2017) and Gong et al., PLoS One 10:e0143272 (2015). Patches of pigmented iPSC-derived RPE cells were microdissociated and plated on laminin-coated plates until confluent. Cell cultures were maintained in RPE cell differentiation medium and allowed to form a monolayer.

[0254] Preparation of RPE cell-derived ECM and nitrite-modified ECM. RPE cell-derived ECM plates were prepared from ARPE-19 cells as described in Wang et al., Curr Eye Res. 30:691-702 (2005); Fields et al. (2017), and Moreira et al., Transl Vis Sci Technol. 4:10 (2015). Two experimental seeding surfaces (untreated ECM and nitrite-modified ECM) were created using ECM on 96-well plates. Nitrite-modified ECM was prepared by adding 100 mM sodium nitrite to the ECM followed by incubation at 37°C for 7 days. Plates were then washed with DPBS and incubated with DPBS for 4 hours to completely remove nitrite.

[0255] Cell viability assay. iPSC-derived RPE cells from AMD donors (n=3, 2 atrophic with GA, 1 exudative) were treated with drugs (elamipretide, Formula IIa compound, ciclopirox olamine, or vehicle) as described below, and iPSC-derived RPE cells from non-disease controls (n=2) were cultured for 24 hours in untreated ECM or nitrite-treated ECM, an in vitro model of Bruch's membrane. Only cells from AMD donors received drugs. The experimental approach is shown in FIG. 8A. Experimental Group: AMD donors only (n=3 individual donors) Cells treated with elamipretide (also referred to as "309" in the figure) at 10 nM, 100 nM, and 1000 nM Cells treated with compound of formula IIa (also referred to as "146c" in the figure) at 10 nM, 100 nM, and 1000 nM Cells treated with the positive control, ciclopirox olamine (also referred to as "ciclopirox" in the figure), at an optimized dose Vehicle-treated cells Non-disease controls (n=2)

[0256] Cell viability was measured by the Real Time-Glo MT Cell Viability Assay (Promega, Madison, WI, www.promega.com) according to the manufacturer's protocol. The assay measures the decreasing electrical potential of viable cells and is adenosine triphosphate (ATP) independent. Luminescence signals were acquired using a BioTek FLx800 plate reader (BioTek).

[0257] Measurement of mitochondrial function. Analysis of mitochondrial function was performed on live iPSC-derived RPE cells from AMD donors (n=3, 2 atrophic with GA, 1 exudative) treated with drugs (elamipretide, compound of formula IIa, or vehicle) and iPSC-derived RPE cells from non-disease controls (n=2) using the XFe96 Extracellular Flux Analyzer (Agilent Technologies, Santa Clara, California, www.agilent.com) and the Seahorse XF Cell Mito Stress Test (CMST) Kit (Agilent Technologies) as described below. iPSC-derived RPE cells were seeded on laminin-coated Seahorse XF plates and grown to confluence. Data were normalized by cell number. Drug treatment was initiated 24 hours prior to assay. Experimental Group: AMD donors only (n=3 individual donors) Cells treated with elamipretide (also referred to as "309" in the figure) at 10 nM, 100 nM, and 1000 nM Cells treated with compound of formula IIa (also referred to as "146c" in the figure) at 10 nM, 100 nM, and 1000 nM Vehicle-treated cells Non-disease controls (n=2)

[0258] Cells were stained with DAPI and counted using ImageJ software (National Institute of Health, Bethesda, Maryland, www.nih.gov). Cells were then washed with CMST assay medium (XF basal medium DMEM, pH 7.4, Agilent Technologies, supplemented with 2 mM glutamine, 5.5 mM glucose, and 1 mM sodium pyruvate) followed by incubation in a non-CO2-free medium. 2The cells were incubated for 1 h at 37° C. in an incubator. The oxygen consumption rate was detected under basal conditions and followed by successive additions of oligomycin, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), rotenone, and antimycin A. From these successive additions, the following parameters could be derived: basal respiration, ATP production, maximal respiration, and spare respiratory capacity.

[0259] Microarray Analysis. iPSC-derived RPE cells from AMD donors (n=3, 2 atrophic and 1 exudative with GA) were treated with drugs (elamipretide or compound of Formula IIa) as described below and cultured in an in vitro Bruch's membrane model for 24 hours. Experimental Group: AMD donors only (n=3 individual donors) Cells treated with elamipretide (also referred to as "309" in the figure) at 10 nM, 100 nM, and 1000 nM Cells treated with compound of formula IIa (also referred to as "146c" in the figure) at 10 nM, 100 nM, and 1000 nM

[0260] Microarray studies using the Affymetrix GeneChip Human Clariom™ S Assay were performed as described in Gong et al. (2020).

[0261] Statistical analysis. Data, statistical analysis, and graphing were performed as described in Gong et al. (2020).

[0262] result: Differentiation of human iPSCs into RPE cells. As shown in Figures 8B-8D, iPSCs from fibroblasts were induced to form embryoid bodies (EBs). The attached EBs then formed neural rosettes before RPE-like cells emerged in culture (Figure 8E). A hexagonal pigmented monolayer of RPE cells formed in culture (Figures 8F and 8G). These iPSC-derived PRE cells expressed RPE markers, including the visual cycle protein retinal pigment epithelium-specific 65 kDa protein (RPE65), the tight junction protein zonula occludens-1 (ZO-1), and sodium-potassium ATPase (NA-K ATPase) (Figure 8H). Figure 8I shows pigmented iPSC-derived RPE.

[0263] Cell viability in nitrite-modified ECM. As shown in FIG. 8J, AMD-derived RPE showed reduced viability in nitrite-modified ECM ("no drug" vehicle-treated cells), but both elamipretide and the compound of Formula IIa significantly enhanced AMD-derived RPE cell viability in nitrite-modified ECM (a model for diseased Bruch's membrane).

[0264] Gene expression profiles in nitrite-modified ECM. As shown in FIG. 8K, hierarchical cluster analysis (HCA) demonstrates that nitrite modification of the ECM induces clustering of gene expression profiles into two distinct groups.

[0265] The effects of elamipretide and the compound of formula IIa on complement-related gene expression were examined. As shown in Figures 8L-8T, ECM nitration increases the expression of complement component genes, particularly complement C1R (C1R), complement component 3 (C3), and complement C4A (C4A). Both elamipretide and the compound of formula IIa reverse this trend (Figures 8L-8P). Both elamipretide and the compound of formula IIa increase the expression of complement regulatory genes, including complement factor H-related protein 2 (CFHR2) (Figure 8S), a major complement regulator that inhibits the C3 alternative pathway. CFHR2 deficiency has been shown to correlate with systemic complement activation and increased risk of AMD. See, e.g., Zhang et al., BMC Med Genet 9:51 (2008); Kubista et al., Mol Vis 17:2080-2092 (2011); Eberhardt et al., PLoS One 8:e78617 (2013); and Cantisilieris et al., Proc Natl Acad Sci USA 115:E4433-4442 (2018).

[0266] Effects of Elamipretide and Formula IIa Compound on Mitochondria-Related Gene Expression. HCA does not appear to distinguish between iPSC-derived RPE with unmodified and nitrite-modified ECM for mitochondrial genes (Figure 8U), however, there are notable changes in individual genes within this group (Figure 8V). As shown in Figures 8W-8Z, both Elamipretide and Formula IIa compound altered the expression of mitochondria-related genes such as CYP24A1 (Figure 8W) and GLS (glutaminase, Figure 8Z). Single point mutations in CYP24A1 (a gene encoding a catabolic enzyme in the vitamin D pathway) have been shown to affect AMD. See Morrison et al., Hum Genomics 5(6):538-568 (2011).

[0267] Mitochondrial Function. As shown in Figures 8AA-8AL, both elamipretide and the compound of Formula IIa demonstrate efficacy in improving mitochondrial function (ATP production (Figures 8AA-8AC), basal respiration (Figures 8AD-8AF), maximal respiration (Figures 8AG-8AI), and spare respiratory capacity (Figures 8AJ-8AL) in AMD-derived RPE cells.

[0268] Conclusion: In summary, these results demonstrate that treatment with elamipretide and the compound of formula IIa significantly improves the ability of AMD-derived RPE cells to survive in nitrite-modified ECM, and treatment with elamipretide and the compound of formula IIa alters the expression of mitochondrial and complement-related genes after nitration of ECM.Thus, these results demonstrate that elamipretide and the compound of formula IIa are useful in methods for treating, preventing, inhibiting, improving, or delaying the onset of age-related macular degeneration, including dry AMD.Furthermore, considering the results and known penetration of peptidomimetics, such as formula IIa), in parts of the eye, and their tendency to target mitochondria, these peptidomimetics are expected to be useful in treating, preventing, inhibiting, improving, or delaying the onset of eye diseases, disorders, and conditions, including but not limited to GA, glaucoma, and / or wet or dry age-related macular degeneration in general. Furthermore, based on these results, administration of the peptide mimetics is expected to be useful for treating, preventing, inhibiting, ameliorating, or delaying the onset of deterioration of (mitochondria-rich) ellipsoid zone health in one or more eyes of a mammalian subject in need thereof.

[0269] Example 3 - Uptake of the compound of formula IIa in ocular tissues in a non-human primate model This example demonstrates that the compound of Formula Ha is taken up by ocular tissue at concentrations typically suitable for producing a therapeutic effect when administered by subcutaneous injection to cynomolgus monkeys for 28 days.

[0270] Abstract This study evaluated the uptake of the compound of Formula Ha in the ocular tissues of cynomolgus monkeys when administered by subcutaneous (SC) injection once daily for 28 days.

[0271] Male and female cynomolgus monkeys were divided into four groups (Groups 1-4). Groups 1 and 4 consisted of 5 males and 5 females, respectively, and Groups 2 and 3 consisted of 3 males and 3 females, respectively. Animals were dosed once daily via SC injection for 28 consecutive days. Animals in Group 1 received the control article, 0.9% Sodium Chloride Injection, USP (Saline). Animals in Groups 2, 3, and 4 received the test article, Compound of Formula IIa, at dose levels of 2, 5, and 15 mg / kg / day, respectively. Three males and three females from Groups 1-3 and three males and one female from Group 4 were necropsied on Day 29 (Terminal Necropsy). Two males and two females from Groups 1 and 4 were necropsied on Day 42 after a 13-day treatment-free period (Recovery Necropsy). Dosing at 15 mg / kg / day (Group 4) was not well tolerated in two females that were necropsied early on Days 25 and 27. Safety endpoints included daily clinical observations and weekly detailed observations, dietary assessments, skin scoring at injection sites, body weights, ophthalmology, electrocardiogram (ECG), hematology, coagulation, serum chemistry, and urinalysis. Blood was collected at multiple time points. At termination, gross observations and organ weights were recorded and eye / optic nerve tissue samples were collected for microscopic evaluation and biodistribution assays.

[0272] method Test Article. The test article was a compound of formula IIa.

[0273] Preparation of Dose Formulations. Dose formulation preparation was performed once a week using clean techniques in a biosafety cabinet. Test article dose formulations were prepared by diluting a stock solution of the compound of Formula IIa at 100 mg / mL (nominal concentration) with an appropriate volume of 0.9% Sodium Chloride Injection, USP. All formulations (including Group 1, control) were filtered using a 0.22 μm polyethersulfone (PES) syringe filter. Osmolality and pH were measured and recorded, and the dose formulations were then aliquoted into a number of sterile glass vials sufficient for daily use over a one week period. All aliquots were stored in a refrigerator set to maintain 4° C. and used within 7 days of preparation.

[0274] On the day of use, each container to be used was removed from 4° C. storage and transferred to the animal room for dosing. Dose administration was completed within 6 hours after removal from 4° C. storage. Any residual dosing formulation remaining in the "Day" container after each day was discarded.

[0275] Test system. The test system was cynomolgus monkeys of Cambodian origin, supplied by Worldwide Primates. Animals were identified by unique skin tattoos. Animals weighed 1.6-2.4 kg and were 2.0-3.1 years old at the start of dosing. For acclimation, there were 18 males and 18 females. For dosing, 16 males and 16 females were used.

[0276] Animal Welfare. The testing facility is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), has an Animal Welfare Assurance approved by the Office of Laboratory Animal Welfare (OLAW), is registered with the United States Department of Agriculture (USDA), and has an Institutional Animal Care and Use Committee (IACUC) that is responsible for the testing facility's compliance with applicable laws and regulations regarding the humane care and use of laboratory animals.

[0277] Housing and environmental conditions. Animals were housed in a temperature- and humidity-controlled environment. Target ranges for temperature and relative humidity were 18-29°C and 30-70%, respectively. An automated lighting system was set to provide a 12-h light / dark cycle. The dark cycle was suspended for study- or facility-related activities. Animals were socially housed in cages that adhered to the recommendations set out in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011).

[0278] Diet and Feeding. PMI's LabDiet® Fiber-Plus® Monkey Diet 5049 was provided at an appropriate daily ration. Animals were fasted prior to blood draws for serum chemistry, urine collection, or when procedures involving sedation or anesthesia were performed. Diet was analyzed routinely for contaminants, none of which were present at levels that would interfere with the outcome of the studies.

[0279] Drinking Water. Fresh drinking water was provided ad libitum. The water was routinely analyzed for contaminants, none of which were present at levels that would interfere with the results of the tests.

[0280] Environmental Enrichment. Fruits, vegetables, treats, and enrichment devices were provided throughout the course of the study.

[0281] Veterinary treatments. No veterinary treatments, such as treatment for diarrhea (Pepto-Bismol / Lactobacillus / Fiber and / or Tylosin), affected any of the animals as test systems to accomplish the study objectives. Diphenhydramine or diazepam was used in some animals as needed if clinical observations of histaminergic or allergic reactions were observed.

[0282] Experimental Design. Animals were transferred to the study from the stock colony at the testing facility. Prior to transfer, selected animals were examined by veterinary staff to ensure adequate health. Animals were acclimated to laboratory procedures for a minimum period of 14 days before dosing began.

[0283] Randomization and Animal Allocation. To control for bias, animals were randomly assigned to groups based on established social units and assigned study-specific animal numbers.

[0284] Test Experimental Design. The test design is shown in Table 4. [Table 4]

[0285] Administration of Dose Formulations. Dose formulations were administered to appropriate animals by subcutaneous injection in the interscapular region using a disposable syringe and needle once daily for 28 days. Four subcutaneous administration sites (upper left / right and lower left / right) were designated on the back using permanent marker or tattoo placement during acclimation, avoiding the spine, with no overlapping edges, and with maximum practical spacing between administration sites. Designated administration sites were shaved and injections rotated between them. If a designated site was not suitable for administration (e.g., due to wound, scab / eschar, etc.), the next most suitable site was used for administration and appropriately documented.

[0286] The SC route of exposure was consistent with the proposed route of administration in humans.

[0287] Clinical Observations. Mortality checks were performed twice daily to assess general animal health and wellness (except on the first and last days of the survival phase, which were performed at least once). Cageside clinical observations were performed once daily, beginning on the second day of acclimation. On dosing days, clinical observations were performed 2 hours (±0.5 hours) after dosing. Detailed clinical examinations were performed on day -1 and then weekly throughout the survival phase (days 7, 14, 21, 28, 29, 35, and 42, pre-dose on dosing days). Animals were placed in treatment cages for examination.

[0288] Body weight. Body weight was measured twice during the acclimation period (including day -1), then weekly during the in-life phase (days 7, 14, 21, 28, 35, and 41) and on the corresponding necropsy day (day 29 or 42).

[0289] Ophthalmology. Ophthalmological examinations were performed once during the adaptation period (day -12) and on day 24 (week 4). Topical mydriatics were administered. No examinations were performed during the recovery period, as there were no findings related to the compound of formula IIa at week 4.

[0290] Necropsy. Animals were fasted overnight prior to termination. Following blood collection on the day of necropsy, animals were sedated, weighed, and euthanized by an overdose of euthanasia solution, followed by a whole body perfusion flush with phosphate buffered saline. Animals were subjected to a complete gross examination and tissue collection. Bone marrow smears were prepared from the sternum at scheduled necropsies. Two females were necropsied early on days 25 and 27. Blood samples (hematology, coagulation, and serum chemistry) were collected prior to euthanasia, followed by a complete gross examination.

[0291] Tissue Collection and Storage. The left eye and optic nerve were fixed in a solution of 2.5% NBF and 3% glutaraldehyde, and the right eye and optic nerve were frozen for biodistribution.

[0292] Biodistribution Analysis - Right Eye and Optic Nerve. After flash freezing in liquid nitrogen for 10-20 seconds, specimens were placed on dry ice and then stored in a freezer set to maintain -80°C. All specimens were shipped frozen on dry ice via overnight carrier to the testing facility for biodistribution analysis of the compound of Formula IIa in the eye and optic nerve.

[0293] A total of 32 cynomolgus monkey eyes were received at the study laboratory. Eyes were stored at -80°C until tissue collection, and aqueous humor (AH), vitreous humor (VH), conjunctiva, cornea, iris / ciliary body (ICB), lens, retina, choroid, optic nerve, and sclera were collected. Methods utilized protein precipitation (PPT) followed by instrumental analysis using HPLC-MS / MS.

[0294] Tissue homogenization. To homogenize ocular tissue samples, weighed amounts of control bovine conjunctiva, ICB, lens, cornea, retina, sclera, choroid, and optic nerve (provided by PharmOptima, Portage, Michigan) were homogenized in USA Scientific impact-resistant microtubes containing 2.8 mm ceramic beads. Unknown cynomolgus monkey conjunctiva, ICB, lens, cornea, retina, sclera, choroid, and optic nerve samples were homogenized in USA Scientific impact-resistant microtubes containing 2.8 mm ceramic beads. Using a diluent of water:acetonitrile:formic acid (75:25:0.1, v / v / v), cornea and conjunctiva samples were diluted 1:19 (tissue:diluent), retina samples were diluted 1:4, sclera, lens, and optic nerve samples were diluted 1:9, and choroid and ICB samples were diluted 1:14. Tissues were homogenized at 5500 rpm for 3 x 30 second cycles (Precellys® development temperature at 4°C) with a 20 second break between cycles. Conjunctival, corneal, choroidal, and scleral samples were run through four homogenizations, while ICB, lens, retina, and optic nerve samples were run through one homogenization.

[0295] Calibration Standards. Stock standards were prepared by individually diluting weighed amounts of the compound of formula IIa with water:formic acid (1000:1, vol / vol) to give a final concentration of 1000 μg / mL. Working stocks were prepared by individually diluting 40 μL of the 1000 μg / mL stock standard with 360 μL of water:formic acid (1000:1, v / v) to give a final concentration of 100 μg / mL of the compound of formula IIa. Working calibration standards of the compound of formula IIa were prepared by serially diluting the working stock standard over a range of 10.0 ng / mL to 20,000 ng / mL. Working calibration standards of the compound of formula IIa were prepared by serially diluting the working stock standard over a range of 50.0 ng / mL to 100,000 ng / mL for the lens samples.

[0296] Quality Control. Stock standards were prepared by individually diluting weighed amounts of compound of formula IIa with water:formic acid (1000:1, vol / vol) to give a final concentration of 1000 μg / mL. Working QC stocks were prepared by diluting 20.0 μL of the 1000 μg / mL stock with 180 μL of water:formic acid (1000:1 v / v) to give a final concentration of 100 μg / mL compound of formula IIa. QC samples were prepared by serially diluting the working QC stock for concentrations in matrix for low, medium, and high QC levels of 6.00, 100, and 1,600 ng / mL. Vitreous humor QCs were prepared by serially diluting the working QC stock for concentrations in matrix for low, medium, and high QC levels of 12.0, 200, and 3,200 ng / mL. Optic nerve QC was prepared by serially diluting the QC stock to concentrations in matrix for low, medium, and high QC levels of 15.0, 500, and 8,000 ng / mL.

[0297] Blanks, blanks with IS, unknowns, and extraction procedures in aqueous humor, vitreous humor, and tissue matrix. To a 2 mL 96-well plate, 100 μL of unknown vitreous humor, aqueous humor, or unknown tissue homogenate, QC, standard, or blank control matrix homogenate) was added. Twenty (20) μL of WIS (Formula IIb at 5000 ng / mL in water:acetonitrile [1:1 v / v]) was added to the blank or 20 μL of acetonitrile:water (1:1 v / v) was added to the double blank (blank without internal standard). Two hundred (200) μL of acetonitrile) was added to all samples. The compound of formula IIb is the deuterated form of the compound of formula IIa. This compound was prepared by substitution of deuterated L-lysine for standard L-lysine in the preparations used to make the compound of formula II and its salts. [ka]

[0298] For optic nerve samples, 50.0 μL of unknown tissue homogenate, QC, standard, or blank control matrix homogenate was added. Twenty (20) μL of WIS (Formula IIb at 5000 ng / mL in water:acetonitrile [1:1 v / v]) was added to the blank or 20 μL of acetonitrile:water (50:50 v / v) was added to the duplicate blank (blank without internal standard). Two hundred (200) μL of acetonitrile was added to all samples.

[0299] Samples were vortex mixed for 5 min and centrifuged at 4000 rpm (4° C.) for 10 min. One hundred (100) μL of water:formic acid (1000:2 v / v) was added to 100 μL of supernatant in a 96-well collection plate, mixed with a multichannel pipette, and analyzed by LC-MS / MS.

[0300] Optic nerve samples were vortex mixed for 5 min and centrifuged at 4000 rpm (4° C.) for 10 min. Two hundred (200) μL of water:formic acid (1000:2 v / v) was added to 50.0 μL of supernatant in a 96-well collection plate, mixed with a multichannel pipette, and analyzed by LC-MS / MS. [Table 5] [Table 6]

[0301] Calculation: Percent coefficient of variation was used as an estimate of precision. Percent coefficient of variation (CV%) = (standard deviation / mean) x 100. Second-order least squares analysis: Standard curve fitting was determined by the 1 / x 2 Quadratic equation with weights: y=ax 2 +bx+c, where y = peak area ratio of the calibration standard to the internal standard, x = concentration of the calibration standard, and a = x 2 a = quadratic coefficient of x, b = quadratic coefficient of x, and c = a constant as the y-intercept of the calibration curve. Quadratic Analyte Concentration: The concentration of the analyte was calculated using the calibration curve parameters calculated above and then solving for the value of x.

[0302] result Concentrations of Drugs in Ocular Matrices. The average concentrations of the compound of Formula IIa in various ocular tissues are shown in Table 5. For the compound of Formula IIa ocular matrices, individual concentration results are included in Tables 6-15. [Table 7] Units: ng / mL, AH and VH; ng / g, sclera, conjunctiva, cornea, lens, ICB, retina, choroid, and optic nerve Day 29 - Final autopsy Day 42 - Recovery Autopsy LLOQ=lower limit of quantitation [Table 8] LLOQ=1.00ng / mL ISD - Insufficient Data for Decision [Table 9] LLOQ=1.00ng / mL ISD - Insufficient Data for Decision [Table 10-1] [Table 10-2] [Table 11-1] [Table 11-2] [Table 12-1] [Table 12-2] [Table 13-1] [Table 13-2] [Table 14-1] [Table 14-2] [Table 15-1] [Table 15-2] [Table 16-1] [Table 16-2] [Table 17-1] [Table 17-2]

[0303] Abstract The data show that the compound of formula IIa accumulates in the ocular tissues of cynomolgus monkeys in a dose-dependent manner when administered subcutaneously, and the concentrations obtained (tens to hundreds of ng / g or more) are expected to be sufficient to provide a therapeutic effect.

[0304] Example 4 - Uptake of the compound of formula IIa in the retina in a non-human primate model This example demonstrates that the compound of Formula Ha, when administered by subcutaneous injection to cynomolgus monkeys for 10 days, is taken up into the retina at concentrations expected to be sufficient to produce a therapeutic effect.

[0305] Abstract The study design is summarized in Table 16 below. [Table 18]

[0306] There were no deaths during the study. No differences in body weight were observed over the course of the study that were considered to be related to administration of the compound of Formula IIa. Administration of the compound of Formula IIa by subcutaneous injection was well tolerated in cynomolgus monkeys at a level of 5 mg / kg / day.

[0307] method Screening and Identification of Animals. Prior to removal from the colony, all animals were subjected to a health assessment to ensure they were healthy and suitable for use in the study. Tattoos and / or subcutaneously implanted electronic identification chips were used for animal identification.

[0308] Acclimatization. At least 5 days were allowed between animal transfer and surgical procedures. A period of at least 5 days was allowed between surgery and the start of dosing.

[0309] Husbandry. Each animal was housed in a separate stainless steel cage. Animals were kept separate during designated procedures / activities and as necessary for monitoring and / or health purposes when deemed appropriate by the Study Director or Clinical Veterinarian. The animal room environment was maintained at a temperature ranging from 18°C ​​to 24°C, 30% to 70% humidity, and 12 hours of light and 12 hours of darkness (except during designated procedures). Animals were fed Envigo Teklad Certified Hi-Fiber Primate Diet No. 7195C twice daily, except during designated procedures. Animals were provided with ad libitum available municipal tap water that had been treated by reverse osmosis and ultraviolet irradiation.

[0310] Veterinary care was available throughout the course of the study and animals were examined by veterinary staff when required by clinical signs or other changes.

[0311] Administration of the compound of formula IIa. The test agent (compound of formula IIa) was administered daily for 10 days via subcutaneous injection in the scapular and dorsal regions. The first day of administration was designated as day 1. Dose formulations were allowed to warm at ambient temperature for at least 30 minutes prior to administration, if necessary. Animals were temporarily restrained and not sedated for dose administration. The volume at each dose was administered in one (preferred) or two (as necessary) separate injections within the designated area. Injection sites were rotated daily as shown in FIG. 9. If a designated injection site was not available for a given animal on any day, the next available test site in the rotation was used. Injection areas were marked as frequently as necessary to allow adequate visualization of the administration sites. At the time of the last injection in each quadrant, the last site of injection was circled and the circled site was collected for necropsy.

[0312] In-life procedures, observations, and measurements. Table 17 summarizes the overall in-life assessments made for each animal. [Table 19]

[0313] Euthanasia Methods: Animals were sedated with an intramuscular injection of a combination of ketamine hydrochloride and acepromazine, then euthanized by an intravenous overdose of sodium pentobarbital, followed by exsanguination.

[0314] Tissue collection, storage, and analysis. Ocular tissues (retina) were collected approximately 24 hours after the last dose on day 10. Left eye tissues (retina) collected for biodistribution analysis were flash frozen in liquid nitrogen, placed in dry ice, and stored at -70°C.

[0315] Tissue samples were prepared and analyzed by methods similar to those described above in Example 3. Briefly, the concentration of the test article (compound of formula IIa) in the retina (ng / g tissue) was determined by LC-MS / MS using compound of formula IIb as the standard.

[0316] result The results are shown in Table 18. [Table 20]

[0317] Abstract The data further show that the compound of formula IIa accumulates in the retina of cynomolgus monkeys when administered subcutaneously, and the concentrations obtained (hundreds of ng / g) are expected to be sufficient to produce a therapeutic effect.

[0318] Equivalent The present technology is not limited with respect to the specific embodiments described in this application, but is intended as a single illustration of each aspect of the technology. As will be apparent to those skilled in the art, many modifications and variations of the present technology can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and devices within the scope of the present technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present technology is limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the present technology is not limited to specific methods, reagents, compounds compositions, or biological systems, which, of course, can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0319] In addition, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0320] As would be understood by one of ordinary skill in the art, for any or all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. Also, as would be understood by one of ordinary skill in the art, all language such as "up to," "at least," "greater than," "less than," etc. refers to a range that includes the recited numbers and can then be broken down into the subranges described above. Finally, as would be understood by one of ordinary skill in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to a group having 1, 2, 3, 4, or 5 cells.

[0321] All patents, patent applications, provisional applications, and publications mentioned or cited in this specification are incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the explicit teachings of this specification.

[0322] Other embodiments are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition for use in a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of an ocular disease, disorder, or condition in a mammalian subject in need thereof, comprising: the method comprises administering to the subject a therapeutically effective amount of at least one peptidomimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof; A pharmaceutical composition, wherein said pharmaceutical composition comprises said at least one peptidomimetic.

2. the peptidomimetic is a peptidomimetic of Formula I, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof; 【Chemical 1】 During the ceremony, A.A. 1 teeth, 【Chemistry 2】 is selected from A.A. 2 teeth, 【Chemistry 3】 is selected from R 1 teeth, 【Chemistry 4】 is selected from R 2a teeth, 【Chemistry 5】 is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is 【Chemistry 6】 is selected from * is the R of X 1 and one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

3. A.A. 1 but, 【Chemistry 7】 is selected from A.A. 2 but, 【Chemistry 8】 is selected from R 1 but, 【Chemistry 9】 is selected from R 2a but, 【Chemistry 10】 is selected from R 2b is H, R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is, 【Chemistry 11】 The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is selected from the group consisting of:

4. A.A. 1 but, 【Chemistry 12】 and AA 2 but, 【Chemistry 13】 and R 1 but, 【Chemistry 14】 and R 2a but, 【Chemistry 15】 and R 7 is H and X is 【Chemistry 16】 The pharmaceutical composition according to claim 3, wherein

5. the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV; 【Chemistry 17-1】 【Chemistry 17-2】 or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

6. 2. The pharmaceutical composition of claim 1, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the ocular disease, disorder, or condition is selected from the group consisting of macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataract, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA).

8. The pharmaceutical composition of claim 1 , wherein the subject is a human.

9. The pharmaceutical composition of claim 1 , wherein the peptidomimetic is administered subcutaneously or intravitreally.

10. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered topically, intraocularly, or ophthalmically.

11. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

12. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

13. The pharmaceutical composition of claim 1, wherein the method further comprises administering an additional treatment to the subject separately, sequentially, or simultaneously.

14. 14. The pharmaceutical composition of claim 13, wherein the additional treatment comprises administration of a therapeutic agent selected from the group consisting of antioxidants, metal complexing agents, anti-inflammatory agents, antibiotics, and antihistamines.

15. The therapeutic agent may be aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demecarium, dexamethasone, dimethicone, benzodiazepine, benzocaine, benzophenone, benzocaine ... Lofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurophate, ketorolac, ketotifen, latanoprost, levobeta amphetamine, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, ranibizumab, rifametidine ...

15. The pharmaceutical composition of claim 14, wherein the compound is selected from the group consisting of mexolone, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinuron, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarubine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations of two or more of the foregoing.

16. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt comprises a tartrate, fumarate, monoacetate, bis-acetate, tri-acetate, mono-trifluoroacetate, bis-trifluoroacetate, trifluoroacetate, monohydrochloride, bis-hydrochloride, trihydrochloride, mono-tosylate, bis-tosylate, or tri-tosylate.

17. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.

18. 10. The pharmaceutical composition of claim 1, wherein the subject has been diagnosed with age-related macular degeneration (AMD).

19. The pharmaceutical composition of claim 1 , wherein the subject has drusen.

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the subject has been diagnosed with geometric atrophy (GA).

21. The pharmaceutical composition of claim 1 , wherein the subject has been diagnosed with glaucoma.

22. (i) an ocular disease, disorder, or condition; or (ii) deterioration of ellipsoid zone integrity; 1. Use of a composition in the preparation of a medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of, in a mammalian subject in need thereof, said composition comprising a therapeutically effective amount of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a peptidomimetic such as a pharmaceutically acceptable salt (e.g., Formula IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof.

23. the peptidomimetic is a peptidomimetic of Formula I, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof; 【Chemistry 18】 During the ceremony, A.A. 1 teeth, 【Chemistry 19】 is selected from A.A. 2 teeth, 【Chemistry 20】 is selected from R 1 teeth, 【Chemical 21】 is selected from R 2a teeth, 【Chemical 22】 is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is 【Chemical 23】 is selected from * is the R of X 1 and one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

24. A.A. 1 but, 【Chemistry 24】 is selected from A.A. 2 but, 【Chemistry 25】 is selected from R 1 but, 【Chemical 26】 is selected from R 2a but, 【Chemical 27】 is selected from R 2b is H, R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is, ​ 24. The use according to claim 23, wherein the compound is selected from the group consisting of:

25. A.A. 1 but, 【Chemical 29】 and AA 2 but, 【Chemistry 30】 and R 1 but, 【Chemical 31】 and R 2a but, 【Chemical 32】 and R 7 is H and X is 【Chemical 33】 25. The use according to claim 24, wherein

26. the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV; 【Hua 34-1】 【Chemistry 34-2】 or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

27. 23. The use of claim 22, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

28. 28. The use of any one of claims 22 to 27, wherein the ocular disease, disorder, or condition is selected from the group consisting of macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataract, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA).

29. 23. The use of claim 22, wherein the subject is a human.

30. 23. The use of claim 22, wherein the medicament is administered subcutaneously or intravitreally.

31. 23. The use of claim 22, wherein the medicament is administered topically, intraocularly, or to the eye.

32. 23. The use of claim 22, wherein the agent is administered orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

33. 23. The use of claim 22, wherein the agent is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

34. 23. The use of claim 22, wherein the subject has been diagnosed with age-related macular degeneration (AMD).

35. 23. The use of claim 22, wherein the subject has drusen.

36. 36. The use of claim 34 or 35, wherein the subject has been diagnosed with geometric atrophy (GA).

37. 23. The use of claim 22, wherein the subject has been diagnosed with glaucoma.

38. (i) an ocular disease, disorder, or condition; or (ii) deterioration of ellipsoid zone health in one or more eyes; 1. A formulation or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of, in a mammalian subject in need thereof, said formulation or medicament comprising a therapeutically effective amount of at least one peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

39. the peptidomimetic is a peptidomimetic of Formula I, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof; 【Chemical 35】 During the ceremony, A.A. 1 teeth, 【Chemical 36】 is selected from A.A. 2 teeth, 【Chemical 37】 is selected from R 1 teeth, 【Chemical Formula 38】 is selected from R 2a teeth, 【Chemical 39】 is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is 【Chemistry 40】 is selected from * is the R of X 1 39. The formulation or medicament of claim 38, wherein said peptidomimetic exhibits a point of attachment to one or more of its hydrogen atoms, optionally substituted with a deuterium or fluorine atom.

40. A.A. 1 but, 【Chemistry 41】 is selected from A.A. 2 but, 【Chemistry 42】 is selected from R 1 but, 【Chemistry 43】 is selected from R 2a but, 【Chemical 44】 is selected from R 2b is H, R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is, 【Chemistry 45】 40. The formulation or medicament of claim 39, selected from:

41. A.A. 1 but, 【Chemistry 46】 and AA 2 but, 【Chemistry 47】 and R 1 but, 【Chemistry 48】 and R 2a but, 【Chemistry 49】 and R 7 is H and X is 【Chemistry 50】 41. The formulation or medicament of claim 40, wherein

42. the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV; 【Chemistry 51-1】 【Chemistry 51-2】 or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of said peptidomimetic are optionally substituted with a deuterium or fluorine atom.

43. 39. The formulation or medicament of claim 38, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the molecule are optionally replaced with a deuterium or fluorine atom.

44. 44. The formulation or medicament of any one of claims 38 to 43, wherein the ocular condition is selected from the group consisting of macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataract, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA).

45. 39. The formulation or medicament of claim 38, wherein the subject is a human.

46. 39. The formulation or medicament of claim 38, wherein the formulation is administered subcutaneously or intravitreally.

47. 39. The formulation or medicament of claim 38, wherein the medicament is administered topically, intraocularly, or to the eye.

48. 39. The formulation or medicament of claim 38, wherein the formulation is administered orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

49. 39. The formulation or medicament of claim 38, wherein the peptidomimetic is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

50. 39. The formulation or medicament of claim 38, wherein the formulation or medicament is prepared by dissolving or suspending the peptidomimetic in a diluent, adjuvant, excipient, or vehicle, such as water or a solvent mixture containing water.

51. 39. The formulation or medicament of claim 38, wherein the subject has been diagnosed with age-related macular degeneration (AMD).

52. 39. The formulation or medicament of claim 38, wherein the subject has drusen.

53. 53. The formulation or medicament of claim 51 or 52, wherein the subject has been diagnosed with geometric atrophy (GA).

54. 39. The formulation or medicament of claim 38, wherein the subject has been diagnosed with glaucoma.

55. 1. A pharmaceutical composition for use in a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of deterioration of ellipsoid zone health in one or more eyes of a mammalian subject in need thereof, comprising: the method comprises administering to the subject a therapeutically effective amount of at least one peptidomimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof; A pharmaceutical composition, wherein said pharmaceutical composition comprises said at least one peptidomimetic.

56. the peptidomimetic is a peptidomimetic of Formula I, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof; 【Chemistry 52】 During the ceremony, A.A. 1 teeth, 【Chemistry 53】 is selected from A.A. 2 teeth, 【Chemical 54】 is selected from R 1 teeth, 【Chemistry 55】 is selected from R 2a teeth, 【Chemical Formula 56】 is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is 【Chemical Formula 57】 is selected from * is the R of X 1 and wherein one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

57. A.A. 1 but, 【Chemistry 58】 is selected from A.A. 2 but, 【Chemical 59】 is selected from R 1 but, 【Chemistry 60】 is selected from R 2a but, 【Hua 61】 is selected from R 2b is H, R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is, 【Hua 62】 57. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition is selected from:

58. A.A. 1 but, 【Chemistry 63】 and AA 2 but, 【Hua 64】 and R 1 but, 【Chemistry 65】 and R 2a but, 【Hua 66】 and R 7 is H and X is 【Hua 67】 57. The pharmaceutical composition of claim 56, wherein:

59. the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV; 【Hua 68-1】 【Hua 68-2】 or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of said peptidomimetic are optionally substituted with a deuterium or fluorine atom.

60. 56. The pharmaceutical composition of claim 55, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

61. 61. The pharmaceutical composition of any one of claims 55-60, wherein the deterioration of ellipsoid zone integrity is associated with an ophthalmic disease, disorder, or condition selected from the group consisting of macular degeneration (including age-related macular degeneration), dry eye, diabetic retinopathy, diabetic macular edema, cataract, autosomal dominant optic atrophy (DOA), Leber's hereditary optic neuropathy (LHON), pigmentary retinopathy, retinitis pigmentosa, glaucoma, ocular hypertension, uveitis, chronic progressive external ophthalmoplegia (e.g., Kearns-Sayre syndrome), and / or Leber's congenital amaurosis (LCA).

62. 56. The pharmaceutical composition of claim 55, wherein the subject is a human.

63. 56. The pharmaceutical composition of claim 55, wherein the peptidomimetic is administered subcutaneously or intravitreally.

64. 56. The pharmaceutical composition of claim 55, wherein the peptidomimetic is administered topically, intraocularly, or ophthalmically.

65. 56. The pharmaceutical composition of claim 55, wherein the peptidomimetic is administered orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

66. 56. The pharmaceutical composition of claim 55, wherein the peptidomimetic is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

67. 56. The pharmaceutical composition of claim 55, wherein the subject has been diagnosed with age-related macular degeneration (AMD).

68. 56. The pharmaceutical composition of claim 55, wherein the subject has drusen.

69. 69. The pharmaceutical composition of claim 67 or 68, wherein the subject has been diagnosed with geometric atrophy (GA).

70. 56. The pharmaceutical composition of claim 55, wherein the subject has been diagnosed with glaucoma.

71. 1. A pharmaceutical composition for use in a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of geometric atrophy in a mammalian subject in need thereof, comprising: the subject has been diagnosed with age-related macular degeneration (AMD); the method comprises administering to the subject a therapeutically effective amount of at least one peptidomimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof; A pharmaceutical composition, wherein said pharmaceutical composition comprises said at least one peptidomimetic.

72. the peptidomimetic is a peptidomimetic of Formula I, or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof; 【Chemical Formula 69】 During the ceremony, A.A. 1 teeth, 【Chemistry 70】 is selected from A.A. 2 teeth, 【Chemical 71】 is selected from R 1 teeth, 【Chemical 72】 is selected from R 2a teeth, [[ID]]【Chemical 73]] is selected from R 2b is H or CH 3 and R 3 and R 4 are independently H and (C 1 -C 6 ) alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl; R 8 and R 9 are independently H, (C 1 -C 6 ) selected from alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; m is 1, 2, or 3; n is 1, 2, or 3; p is 0 or 1; X is 【Chemical 74】 is selected from * is the R of X 1 and one or more of the hydrogen atoms of the peptidomimetic are optionally substituted with a deuterium or fluorine atom.

73. A.A. 1 but, 【Chemistry 75】 is selected from A.A. 2 but, 【Chemical 76】 is selected from R 1 but, 【Chemical 77】 is selected from R 2a but, 【Chemical 78】 is selected from R 2b is H, R 3 and R 4 is independently selected from H and methyl; R 5 and R 6 is independently selected from H and methyl; R 7 is selected from H and methyl; R 8 and R 9 is independently selected from H and methyl; X is, 【Chemical 79】 73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is selected from:

74. A.A. 1 but, 【Chemistry 80】 and AA 2 but, 【Chemistry 81】 and R 1 but, 【Chemistry 82】 and R 2a but, 【Chemistry 83】 and R 7 is H and X is 【Chemistry 84】 73. The pharmaceutical composition of claim 72, wherein:

75. the peptidomimetic is a peptidomimetic of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV; 【Chemistry 85-1】 【Chemistry 85-2】 or a pharmaceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of said peptidomimetic are optionally substituted with a deuterium or fluorine atom.

76. 72. The pharmaceutical composition of claim 71, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Formula II), or a pharmaceutically acceptable salt (e.g., IIa), stereoisomer, tautomer, hydrate, and / or solvate thereof, wherein one or more of the hydrogen atoms of the peptidomimetic are optionally replaced with a deuterium or fluorine atom.

77. A pharmaceutical composition described in any one of claims 71 to 76, wherein administration of the peptide mimetic delays the onset of deterioration of ellipsoid zone integrity in one or both eyes of the subject.

78. 72. The pharmaceutical composition of claim 71, wherein the subject is a human.

79. 72. The pharmaceutical composition of claim 71, wherein the peptidomimetic is administered subcutaneously or intravitreally.

80. 72. The pharmaceutical composition of claim 71, wherein the peptidomimetic is administered topically, intraocularly, or ophthalmically.

81. 72. The pharmaceutical composition of claim 71, wherein the peptidomimetic is administered orally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, or intramuscularly.

82. 72. The pharmaceutical composition of claim 71, wherein the peptidomimetic is administered daily for 2 weeks or more, 12 weeks or more, 24 weeks or more, 52 weeks or more, or 2 years or more.

83. 72. The pharmaceutical composition of claim 71, wherein the subject has drusen.

84. 84. The pharmaceutical composition of claim 83, wherein the subject has been diagnosed with geometric atrophy (GA).

85. 72. The pharmaceutical composition of claim 71, wherein administration of the peptidomimetic delays the onset of geometric atrophy in a mammalian subject diagnosed with age-related macular degeneration.

86. 72. The pharmaceutical composition of claim 71, wherein administration of the peptidomimetic inhibits the development of geometric atrophy in a mammalian subject diagnosed with age-related macular degeneration.

87. 72. The pharmaceutical composition of claim 71, wherein administration of the peptidomimetic prevents geometric atrophy from developing in a mammalian subject diagnosed with age-related macular degeneration.

88. The pharmaceutical composition of any one of claims 85 to 87, wherein the subject has drusen.

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