WO2011054993A1 - Peptides for the treatment of ocular hypertension and/or glaucoma - Google Patents

Abstract

The invention relates to peptide compounds with the amino acid sequence having formula (I): Tyr-Ala-Arg-Ala-Ala-Ala-Arg-Gln-Ala-Arg-Ala-(X)-Ser-Asp-Gly-Gly-pTyr-Met- Asp-Met-Ser (I), wherein (X) is none, one or more amino acid spacer residues and pTyr is a phosphorylated tyrosine, and variants and derivatives of said compounds, which can be used in medicine to reduce intraocular pressure. The peptides or the pharmaceutical compositions containing same can be used for the treatment and/or prevention of ocular hypertension and/or glaucoma.

Description

 Peptides for the treatment of ocular hypertension and / or glaucoma

The present invention is generally framed in the field of medicine and specifically in the field of ophthalmology. In particular, the invention relates to compounds for the treatment of glaucoma and / or ocular hypertension.

STATE OF THE TECHNIQUE Glaucoma is characterized by producing a lesion in the head of the optic nerve accompanied by a decrease in the normal visual field. An elevated intraocular pressure (hereinafter IOP) constitutes a risk factor for the loss of glaucomatous visual field. Around 67 million people in the world have glaucoma, and between 5 and 8 million of them are blind. According to some estimates, some 100 million more people have high IOP and would be at risk of having significant vision problems.

Although the causes of glaucoma are not fully known, its symptoms, in most cases, include an elevated IOP that can be caused by overproduction or by an inappropriate elimination of aqueous humor. The elevation of the IOP is associated with clinical manifestations characteristic of glaucomatous optic neuropathy. Optic nerve dysfunction could be the result of changes in pressure at the level of the structure of the optic nerve head and / or a low blood supply in the head of the optic nerve and in the retina. The absence of treatment or inadequate treatment of glaucoma can lead to significant loss of vision or total blindness. In cases where surgery is not advised, various drugs are useful for the treatment of glaucoma. These include: miotics (e.g.

pilocarpine, carbacol, and acetylcholinesterase inhibitors);

sympathomimetics (eg epinephrine, dipivalylepinephrine and apraclonidine); beta-blockers (eg betaxolol, levobunolol and timolol); and carbonic anhydrase inhibitors (eg dorzolamide hydrochloride, acetazolamide,

methazolamide and ethoxyzolamide). It is accepted that the miotics and

sympathomimetics decrease IOP by increasing evacuation flow of aqueous humor, while beta-blockers and carbonic anhydrase inhibitors decrease IOP by reducing the formation of aqueous humor. The four types of drugs have potentially serious side effects. Miotics such as pilocarpine can cause blurred vision and other side effects in vision, which leads to a sick person's discomfort or abandonment of treatment. Carbonic anhydrase inhibitors can also have important effects.

side effects that affect the patient's well-being and / or abandonment of treatment. In addition, at least one beta-blocker, timolol, has frequently been associated with important pulmonary side effects that are attributed to its effect on beta-2 receptors present in lung tissue. Recently, prostaglandin analogues have proven useful in the treatment of glaucoma topically. These compounds decrease IOP by increasing the flow of evacuation of aqueous humor through the uveoscleral route.

Consequently, there is a continuing need for alternative therapies to control the elevated IOP associated with glaucoma, trying to lessen the adverse effects of current therapies.

EXPLANATION OF THE INVENTION

The inventors provide a new approach for the treatment of glaucoma and ocular hypertension that involves the use of peptide compounds, or their pharmaceutically acceptable salts, selected from the group consisting of: (i) a peptide with the amino acid sequence of formula (I ):

Tyr-Ala-Arg-Ala-Ala-Ala-Arg-Gln-Ala-Arg-Ala- (X) -Ser-Asp-Gly-Gly-pTyr-Met- Asp-Met-Ser (I) where (X) it is none, one or more amino acid residues spacers, and pTyr is a phosphorylated tyrosine; (ii) a variant of the peptide of formula (I) that has substitution, elimination and / or addition of amino acid residues along the amino acid sequence, and / or that has another addition of 1 to 10 amino acid residues in the N and / or C terminal ends of the sequence; and (iii) a peptide derivative of formula (I) having chemical modifications in amino acid residues. The peptide compounds have at least 80% sequence identity with the peptide of SEQ ID NO: 1, and have the ability to activate phosphatidylinositol-3-kinase

("phosphatidylinositol-3-kinase", Pi3K).

The peptide compounds of the invention show important differences with commercial drugs normally used in the treatment of ocular hypertension. The peptide with sequence SEQ ID NO: 1 has greater effects than any of the commercial drugs tested: IOP reduction of 49% versus 35.3% obtained with timolol

(Timoftol ^® ). The application of this peptide implies a maximum reduction of the IOP greater and of lasting effect. The peptide compounds of the invention do not act by stimulating a receptor (unlike carbacol), or activating a tyrosine kinase receptor (as opposed to platelet-derived growth factor or PDGF), or antagonizing a receptor (a unlike timolol), nor inhibiting an enzyme (unlike dorzolamide). In contrast, the peptide compounds of the invention act through the activation of Pi3K, recruiting the Pi3K complex to the membrane and inducing its activation. This represents a new pharmacological target not previously described for the control of ocular hypertension.

Thus, the present invention relates to peptide compounds with the amino acid sequence of formula (I), as well as variants or derivatives of said peptide.

Part of the present invention are variants of the peptide of formula (I), subject to substitution, addition and / or elimination of amino acids. The amino acids can be substituted by other amino acids selected from natural amino acids or from unnatural / modified amino acids. The amino acid substitution may be conservative (i.e. substituted by other residues with similar physicochemical properties) or non-conservative (i.e. substituted by other residues with different physicochemical properties) but without implying a substantial alteration of the primary structure. The peptide may have another addition of between 1 and 10 amino acid residues added at the N and / or C terminal ends of the sequence. The

substitutions, deletions or additions are selected so that no affect peptide activity.

Also suitable for the eye treatment described in accordance with the invention are those derived from the peptide of formula (I) which have

chemical modifications in amino acid residues. Derivatives

Particularly suitable are those amidated, acetylated, sulfated, phenylated, alkylated phosphorylated, glycosed, oxidized or modified with polyethylene glycol. The modifications are selected so as not to affect the activity of the peptide.

Preferred modifications for the peptide of formula (I) are the amidation of the C-terminal end to prevent degradation thereof; the replacement of aspartic acid and glycine (positions 14 and 15 of formula (I)) to avoid spontaneous hydrolysis; and the substitution of methionine (formula (II)) with norleucine (formula (III)) to avoid spontaneous oxidation of methionine. Thus, in a particular embodiment of the invention, the peptide compound has one or both Met substituted by norleucine (Nle).

 formula (III)

Derivatives and variants of the peptide of formula (I) have at least 80% identity in sequence with the peptide of SEQ ID NO: 1, and have the ability to activate Pi3K. This activity is preferably established in an assay where phosphorylation levels of Akt are measured. Akt or PKB (protein kinase B) is an effector of Pi3K found further down in the signaling cascade. In the description of particular embodiments a suitable test is described. The basal levels of phosphorylated Akt (p-Akt) are very low, so the activation of Akt and, consequently, the Pi3K activation means an increase of this basal level. The activation percentage was calculated as the p-Akt level after treatment. compared to the level of p-Akt under control conditions. After 30 minutes of treatment with the peptide of SEQ ID NO: 1 an increase of 50% was achieved with respect to the basal level of p-Akt, and 55% after 180 min. Particularly suitable variants are those in which pTyr (formula (IV)) has been replaced by a birradical selected from the group consisting of 4-sulfophenylalanine (formula (V)), 4-carboxy-L-phenylalanine (formula (VI)) , N- (oxalyl) -4-aminophenylalanine (formula (VII)), N- (sulfo) -4-aminophenylalanine (formula (VIII)), 4- (sulfomethyl) -phenylalanine (formula (IX)), N- ( 2-sulfoethyl) -L- asparagine (formula (X)), N- (sulfomethyl) -L-asparagine, 4- (phosphonomethyl) -L- phenylanaline (formula (XI)), N ⁸ -oxalyl-ornithine and S- (2-sulfoethyl) cysteine.

 formula (IV)

formula (VII) formula (VIII) formula (IX)

 formula (X) formula (XI)

The formulas indicate the anionic form of the amino acid residue.

These variants were found using the peptide of SEQ ID NO: 1 as a reference molecule in a screening of potential peptide analogs. Screening first took into account mimicking the physicochemical properties of the peptide. Since the molecular field of a molecule represents its interaction with another entity (for example, a protein), two molecules with a similar molecular field are expected to have the same function, in this case, a biological function. Then, to get a better analysis, the best molecules of the first screening were subjected to a docking procedure considering the properties of the target. In this way, the variants found mimic the peptide of SEQ ID NO: 1.

In another particular embodiment, the peptide compound has the amino acid sequence of formula (I) where (X) is none, one or more spacer amino acid residues, and pTyr is a phosphorylated tyrosine. In a more particular embodiment, (X) is a glycine residue. More particularly, the peptide compound has the sequence SEQ ID NO: 1.

In other particular embodiments, the peptide compound has an amino acid sequence selected from the group consisting of SEQ ID NO: 2-22.

The peptide compounds of the invention can be synthesized by any method analogous to those detailed herein, including, but not limited to, solid phase synthesis, liquid phase synthesis, protein expression by transformed cells, excision of a synthetic or semi-synthetic polypeptide, or a combination of these methods. The amino acids that make up the sequence may have an L or D configuration. Those with a D configuration are more expensive, but more resistant to degradation by proteases.

Peptide compounds according to the present invention, in the form of pharmaceutically and / or biologically acceptable salts such as sodium, potassium, calcium, magnesium salt or acid addition salts, can also be obtained by methods analogous to those described herein. . Examples of these latter salts include salts of inorganic acids (eg hydrochloric acid, sulfuric acid and phosphoric acid) and organic acids (eg acetic acid, propionic acid, citric acid, tartaric acid, malic acid and acid

methanesulfonic acid).

Another aspect of the invention relates to the peptide compounds of the invention for use in medicine. Another aspect of the invention relates to the use of the peptide compounds of the invention for the manufacture of a medicament for reducing intraocular pressure. They can also be used for the manufacture of a medicament for the treatment and / or prevention of ocular hypertension and / or glaucoma. This aspect can also be expressed as referring to a method for the treatment and / or prevention of glaucoma and / or ocular hypertension in a mammal, including a human, where an effective amount of the peptide compound of the invention is administered to the affected eye. of said mammal or human.

The peptide compound of the invention could additionally be combined or linked to other sequences such as histidine sequences to allow purification of the peptide, or to antigenic sequences such as hematoglutinin, T7 or myc, to recognize the peptide compound.

Another aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the peptide compound of the invention, together with sufficient amounts of excipients.

pharmaceutically acceptable. In a particular embodiment, the excipients Pharmaceutically acceptable are appropriate for topical ophthalmic administration, that is, suitable for use in contact with eye tissues without inducing toxicity, irritation, incompatibility, instability, allergic response or the like.

The amount of peptide compound of the invention to be administered can be determined without too much experimentation by a person skilled in the art. Due to the direct transduction of the peptide compound after its corneal application, the effective amount necessary to have a therapeutic effect is less than with other antiglaucomatous drugs. In general, amounts between 0.1 and 1 μg ml, and preferably 0.5 μg ml, are used for topical administration.

As those skilled in the art will appreciate, the compositions can be prepared in different dosage forms suitable for topical ophthalmic application, including solutions, suspensions, emulsions, gels, creams, ointments and sprays.

Additionally, to ophthalmological forms of topical application, the peptide compound may be administered through other forms, such as direct injection into the anterior chamber of the eye, or by any type of slow-release system.

The compositions of the present invention may comprise

additionally components that allow a controlled release or greater comfort. These components include mucomimetic polymers, thickener gels based on polysaccharides or finely divided drug transporting substrates. In addition, the compositions of the invention may comprise various ingredients as preservatives.

antimicrobials and toning agents to adjust the osmolarity of the compositions. Depending on the disease, the compositions may comprise the peptide compound as a single agent for the treatment of ocular hypertension and glaucoma, or combinations of several of these compounds, or combinations with other therapeutic agents.

Unless defined otherwise, all the technical and scientific terms used here have the same meaning as those commonly understood by a person skilled in the field of the invention. Methods and materials similar or equivalent to those described herein may be used in the practice of the present invention. Throughout the description and the

claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following particular embodiments and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of the particular and preferred embodiments described herein.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect on IOP after a single application of a 10 μΙ drop of the peptide of SEQ ID NO: 1, at a concentration of 0.5 Mg / μΙ. As the figure indicates, the maximum reduction in IOP was obtained after five hours, "t (h)" means time in hours; "pep" means peptide; "with" means saline control. FIG. 1 refers to the "Single application" section of the description of particular embodiments.

FIG. 2 shows the effect on IOP after applying 10 ng of platelet-derived growth factor (PDGF) in a final volume of 10 μΙ. IOP is represented as% of the control, "t (h)" means time in hours; "go" means vehicle. FIG. 2 refers to the "Comparison of the Peptide with PDGF" section of the description of particular embodiments.

FIG. 3 shows a graph of IOP levels during a five-day treatment with the peptide of SEQ ID NO: 1. The arrows indicate the time of the different applications, "t (h)" means time in hours; "pep" means peptide. FIG. 3 refers to the "Chronic application" section of the

description of particular embodiments. FIG. 4 shows the increase in p-Akt levels induced by the peptide of SEQ ID NO: 1. The ability of the peptide to activate the Pi3K-Akt-GSK3 signaling pathway was quantified by measuring p-Akt levels in the Ser-473 position using a SH-SY5Y human glioma cell line. The cells were fasted in serum for 16 hours before the peptide was added. Quantification shows that p-Akt levels increased to a maximum after 60-120 minutes and remained constant during the time interval examined (6 hours), "t (min)" means time in minutes. FIG. 4 refers to the "Quantification of Pi3K activity by Western Blot" section of the description of particular embodiments. FIG. 5 shows the reduction of the IOP ("IOP network" in mm Hg) during a five-day treatment with the Peptide to the left eyes of the rats (LE) and with saline (control) to the right eyes (RE) . 1, 2, 3, 4 and 5 are the days of treatment. Treatment measures are indicated with striped pattern bars while control measures with smooth bars.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS Animals

White rabbits from New Zealand, weighing 2-2.5 kg, were kept in individual cages, with food and water ad libitum as described above (cf. M. Morales et al., "Hypotensive effect of profilin on rabbit intraocular pressure" , Eur J Pharmacol 2007, vol. 567, pp. 145-8). The animals used were housed following a controlled cycle of 12 h / 12 h light / dark. All the protocols used complied with the ARVO Statement for the Use of Animáis in Ophthalmology and Vision Research and with the European Communities Council Directive 86/609 / EEC. Peptide formulation and method of administration

The peptide with sequence: Tyr-Ala-Arg-Ala-Ala-Ala-Arg-GIn-Ala-Arg-Ala Gly-Ser-Asp-Gly-Gly-pTyr-Met-Asp-Met-Ser (SEQ ID NO: 1) will be called next "The Peptide". It was obtained by solid phase peptide synthesis. The Peptide was formulated in isotonic saline solution and used at a

final concentration of 0.5 μς / μΙ. The Peptide was applied unilaterally to the cornea at a fixed volume of 10 μΙ. The contralateral eye received the same volume of control solution (0.9% NaCI, vehicle). Since tonometry can cause some discomfort in rabbits, the corneas were anesthetized by applying 10 μΙ of a 1: 10 (v: v) solution of oxybuprocaine / tetracaine (4 mg and 1 mg respectively, from Alcon Cusí, Barcelona, Spain) .

The ΙΟΡ was measured once every 30 minutes during the first hour and then once every hour. The instillation time was considered time 0.

The experiments were performed following a blind protocol: the researcher did not receive any information about the nature of the agent (Peptide or vehicle). The mediciones measurements were made with a Tonopen ^® XL contact tonometer at baseline (pretreatment) and at the indicated times after instillation of the compound. The ΙΟΡ was recorded for 8 hours, to study the temporal development of the effects. During one day of experimentation, only one dose was tested, which was washed for at least two days between doses.

Single application

To study the effects of Peptide on ΙΟΡ of rabbits, a single application was tested following the conditions described above. Only one drop (10 μΙ) was applied at a concentration of 0.5 μ9 / μΙ unilaterally. The ΙΟΡ measurements began 30 minutes before the instillation of the agent. The zero time was set as the agent application time. Subsequently the measurements were made every hour. The application of the Peptide induced a significant reduction of ΙΟΡ which was maximum four hours after instillation of the compound. The average reduction of ΙΟΡ from 8 different animals was 49.5 ± 1 .8%. The ΙΟΡ reduction remained significantly below the control levels for the next four hours (n = 8; FIG. 1). As a control, the same experiment was performed independently testing only saline solution. In no condition did the IOP show significant changes (n = 8, FIG. 1). Comparison of the Peptide with commercial drugs

The reduction of the IOP obtained with the Peptide indicates a better

behavior than that of commercial hypotensive drugs

commonly used in the treatment of intraocular pressure. For this purpose, the effect of the Peptide was compared with three different drugs with three different pharmacological mechanisms. The drugs were tested

dorzolamide (Trusopt ^® ), timolol (Timoftol ^® ) and pilocarpine (Colircusí

pilocarpine) regarding its ability to regulate IOP (n = 6), and the results were compared with those of the Peptide. All drugs were tested applying a volume of 40 μΙ. The following table summarizes the results. The percentage indicates the maximum reduction of the IOP.

TABLE 1

Comparación del Péptido con PDGF

Comparison of the Peptide with PDGF

Since The Peptide mimics the intracellular domain of the activated form of the PDGF receptor, theoretically, it should produce results similar to those of the PDGF application. For this purpose, changes in IOP levels were studied after a 10 ng corneal application of PDGF (in a final volume of 10 μΙ).

As indicated in FIG. 2, the application of PDGF only decreased IOP levels up to 20%, and the reduction only lasted 3-4 hours. In summary, the peptide of the invention has a better range of effects, reduction of the maximum IOP and more lasting effects than those obtained after the application of PDGF. Chronic application

To study the effects of repeated exposure of the Peptide, a chronic treatment experiment was performed. To this end, five animals were treated each day with a single dose of the Peptide for a period of five days. IOP was measured every day after 5 and 8 hours after instillation. The results (FIG. 3) indicate that repeated application always induces the same degree of IOP decrease, without desensitizing. It is important to note that the baseline IOP levels measured during the second and following days were not fully recovered, indicating a time effect window greater than 24 hours.

Data analysis

Numerical values are represented as mean ± standard error of the mean (ESM). The means between groups were compared using the t-Student test (unpaired, two tails) with a 5% significance. Quantification of Pi3K activity using Western Blot

The Peptide's ability to activate Pi3K was monitored by measuring phosphorylation levels of the Akt protein, an effector of Pi3K. Cultures of the human glioma cell line (SH-SY5Y) were treated in serum fasting, with a concentration of 50 g / ml of the Peptide. P-Akt levels were quantified at 10, 30, 120, 180 and 360 minutes after application of the peptide. The cells were grown in 12 mm diameter plates and washed twice with PBS (4 ° C). They were scraped and lysed with 300 μΙ of lysis buffer solution containing: 62.5 mM Tris HCI, pH 6.8, 2% SDS, 10% glycerol, 100 mM DTT and 0.01% bromophenol. Cell lysates were collected and heated at 85 ° C for 3 minutes. They were sonicated for 5 minutes and finally clarified by centrifugation at 17,000 g. The supernatants were stored frozen at -80 ° C. The samples were passed through a 12% SDS-PAGE gel and Western blotting using two specific antibodies: one against Akt and a second against p-Akt. The signal was detected using a chemiluminescent detection system. Activity levels are expressed as the ratio of the optical density of p-Akt divided by its corresponding total level of Akt. The Peptide induced a stable increase in p-Akt up to 50% activation after 30 minutes and 55% after 180 minutes (see FIG. 4). In vivo evaluation of IOP reduction in an induced glaucoma model

The objective of the study was to evaluate the reduction of IOP in an animal model of induced glaucoma. The selected model was the cauterization of three episcleral veins that causes an extension of cell death equivalent to human glaucoma.

Three-year-old female Sprague-Dawley rats weighing approximately 250 g were used in this study. For all rats, the left eyes (LE) were subjected to cauterization of the episcleral veins (CEV) following the protocol described in J.H. Urcola et al., "Three experimental glaucoma models in rats: Comparison of the effects of intraocular pressure elevation on retinal ganglion cell size and death", Experimental Eve Research 2006, vol. 83, pp. 429-37. Briefly, two dorsal episcleral veins located near the superior rectus muscle, and a temporal episcleral vein near the lateral rectus muscle were isolated from surrounding tissues. A specific and precise cauterization was applied to the vein

selected being careful not to cause thermal damage to other neighboring tissues. After the procedure, an antibiotic-steroidal ointment containing chloramphenicol was applied to the surface of the eye

dexamethasone. No surgery was applied to the right eyes (RE), which were used as a control.

Measurement of intraocular pressure: IOP measurements were performed with a Tonopen ^® XL contact tonometer at baseline (pretreatment) and at the times indicated after instillation of the compound. The rats were kept awake (not anesthetized) and a single drop of local anesthetic was applied to the eye before measurement. The person responsible for taking the measures was always the same person to avoid possible modifications in the measurement methodology and to avoid the stress of the rat. The measurements were always taken at the same time of day. The first measure began at 9 am and the second after treatment began at 1 pm. The measurements were taken in the same order of the rats to keep the times between measurements.

Treatment methodology: the LOPs of LE and RE were measured at 9 a.m. Immediately afterwards, a 10 μΙ drop of saline solution was instilled in the ER and 10 μΙ of the Peptide in the LE: Four hours after instillation, all rats for both eyes were measured in the same order. The next day, the LOPs were measured at 9 a.m. before applying the new drop to the rat. These measures, 24 hours after the first drops, serve to know if the effect of the treatment is maintained in the long term (24 hours). The treatment was applied for five consecutive days.

Controls: the ER of each rat was used as a control to verify that there was no effect on the IOP by the vehicle (saline solution).

Conclusion: FIG. 5 shows that the application of the Peptide induced a significant reduction in IOP 4 hours after the instillation of the Peptide. The reduction in the level of IOP remained significantly below the control value during all the days studied.

Claims

REVINDICATIONS one . Peptide compound, or its pharmaceutically acceptable salts, selected from the group consisting of: (i) a peptide with the amino acid sequence of formula (I): Tyr-Ala-Arg-Ala-Ala-Ala-Arg-Gln-Ala-Arg-Ala- (X) -Ser-Asp-Gly-Gly-pTyr-Met- Asp-Met-Ser (I) where (X) it is none, one or more amino acid residues spacers, and pTyr is a phosphorylated tyrosine; (ii) a variant of the peptide of formula (I) that has substitution, elimination and / or addition of amino acid residues along the amino acid sequence, and / or that has another addition of 1 to 10 amino acid residues in the N and / or C terminal ends of the sequence; Y (iii) a peptide derivative of formula (I) having chemical modifications in the amino acid residues; where the peptide compound has at least 80% sequence identity with the peptide of SEQ ID NO: 1, and has the ability to activate phosphatidylinositol-3-kinase (Pi3K). 2. A peptide compound according to claim 1, which is a variant wherein pTyr has been replaced by a birradical selected from the group consisting of 4-sulfophenylalanine, 4-carboxy-L-phenylalanine, N- (oxalyl) -4-aminophenylalanine, N - (sulfo) -4-aminophenylalanine, 4- (sulfomethyl) -phenylalanine, N- (2-sulfoethyl) -L- asparagine, N- (sulfomethyl) -L-asparagine, 4- (phosphonomethyl) -L-phenylanaline, Ν ^δ -oxalyl-ornithine and S- (2-sulfoethyl) cysteine. 3. A peptide compound according to any one of claims 1-2, wherein one or both Met have been replaced by norleucine (Nle). 4. A peptide compound according to claim 1, which is a peptide with the amino acid sequence of formula (I) wherein (X) is none, one or more spacer amino acid residues, and pTyr is a phosphorylated tyrosine. 5. A peptide compound according to any of claims 1-4, wherein (X) is a glycine residue. 6. A peptide compound according to claim 5, having the sequence SEQ ID NO: 1. 7. A peptide compound according to any one of claims 1-5, which has an amino acid sequence selected from the group consisting of SEQ ID NO: 2-22. 8. Peptide compound as defined in any of claims 1-7, for use in medicine. 9. Peptide compound as defined in any one of claims 1-7, for use in reducing intraocular pressure. 10. Peptide compound as defined in any of the claims 1-7, for use in the treatment and / or prevention of ocular hypertension and / or glaucoma. eleven . Use of the peptide compound as defined in any of claims 1-7, for the manufacture of a medicament for the reduction of intraocular pressure. 12. Use of the peptide compound as defined in any one of claims 1-7, for the manufacture of a medicament for the treatment and / or prevention of ocular hypertension and / or glaucoma. 13. Pharmaceutical composition comprising an amount Therapeutically effective peptide compound as defined in any of claims 1-7, together with sufficient amounts of pharmaceutically acceptable excipients. 14. Pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable excipients are suitable for topical ophthalmic administration.