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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
  • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is generally related to treatments for ocular disorders and more specifically to the use of agents that lower IOP and/or treat or prevent glaucoma.
• POAG Primary open angle glaucoma
• POAG also known as chronic or simple glaucoma
• POAG represents the majority of all glaucomas in the United States.
• Most forms of glaucoma result from disturbances in the flow of aqueous humor that have an anatomical, biochemical or physiological basis.
• PAI-I plasminogen activator inhibitor- 1
• tPA tissue plasminogen activator
• uPA urokinase plasminogen activator
• Plasmin is known to promote the conversion of certain pro-matrix metalloproteinases (MMPs) into their active, extracellular matrix (ECM)-degrading, forms (He et al., PNAS, 1989).
• MMPs pro-matrix metalloproteinases
• ECM extracellular matrix
• PAI-I also modulates the association of vitronectin, an ECM component, with cell surface integrins which act as adhesion receptors (Zhou et al., Nature Structural Biology, 2003).
• PAI-I has been linked to both decreased adhesion and increased detachment of cells in non-ocular tissues.
• Drug therapies that have proven to be effective for the reduction of IOP (IOP) and/or the treatment of POAG include both agents that decrease aqueous humor production and agents that increase the outflow facility.
• Such therapies are in general administered by one of two possible routes; topically (direct application to the eye) or orally.
• pharmaceutical ocular anti-hypertension approaches have exhibited various undesirable side effects.
• miotics such as pilocarpine can cause blurring of vision, headaches, and other negative visual side effects.
• Systemically administered carbonic anhydrase inhibitors can also cause nausea, dyspepsia, fatigue, and metabolic acidosis.
• Certain prostaglandins cause hyperemia, ocular itching, and darkening of eyelashes and periorbital skin.
• Embodiments of the present invention recognize that the modulation of PAI-I binding to vitronectin can be used to treat ocular disease and/or lower IOP.
• One embodiment provides a method for treating glaucoma or elevated IOP in a patient comprising administering to the patient an effective amount of a composition comprising an agent that modulates PAI-I binding to vitronectin.
• Another embodiment of the present invention is a method of treating a PAI-I- associated ocular disorder comprising administering an effective amount of a composition comprising an agent that modulates PAI-I binding to vitronectin.
• the agent is ZK4044, PAI-039, WAY- 140312, HP-129, T-686, XR5967, XR334, XR330, XR5118, PAI-I antibodies, PAI-I peptidomimetics, and combinations thereof.
• Yet another embodiment is a method of manufacturing a compound to be used as a treatment for glaucoma or elevated IOP comprising providing a candidate substance suspected of modulating PAI-I binding, selecting the compound by assessing the ability of the candidate substance to decrease the amount of active PAI- 1 in the trabecular meshwork of a subject suffering from glaucoma or elevated PAI-I, and manufacturing the selected compound.
• compositions of the invention further comprise a compound selected from the group consisting of ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, gelling agents, hydrophobic bases, vehicles, buffers, sodium chloride, water, and combinations thereof.
• a compound selected from the group consisting of ⁇ -blockers, prostaglandin analogs, carbonic anhydrase inhibitors, ⁇ 2 agonists, miotics, neuroprotectants, rho kinase inhibitors, and combinations thereof may be administered either as part of the composition or as a separate administration.
• PAI-I has been linked to both decreased adhesion and increased detachment of cells in non-ocular tissues.
• a review of the data disclosed herein leads to the conclusion that increased PAI-I levels in glaucomatous aqueous humor may be due to actions of TGF ⁇ 2 on trabecular meshwork cells.
• PAI-I -induced decreases in TM cell adhesion are likely due to PAI-I interference with attachment of cells to the extracellular matrix component vitronectin. Additionally, the PAI-I -induced decrease in TM cell adhesion may facilitate migration of TM cells from the meshwork environment.
• PAI-I induced decrease in TM cell adhesion and increase in TM cell migration may be important factors in the decrease of TM cellularity seen in glaucomatous eyes.
• Certain embodiments of the present invention recognize that PAI-I may cause such effects in trabecular meshwork (TM) tissues.
• Circulating PAI-I normally exists in a latent form, due to the ability of the active PAI-I to rapidly and spontaneously transform to its inactive conformation.
• PAI-I bound to vitronectin becomes stabilized in its active form, resulting in a much longer half-life.
• one means to reduce deleterious effects of active PAI-I is to utilize agents which modulate the interaction of PAI-I and vitronectin. Such agents would thus allow unbound vitronectin in the ECM to associate with its cell surface (integrin) receptors, thus enhancing cellular adhesion and reducing cell loss from TM tissues. Modulation of PAI-I 's ability to bind vitronectin can provide a viable therapeutic approach to the management of glaucoma.
• Certain embodiments of the present invention are methods for targeting the downstream effects of PAI-I in ocular disorders such as glaucoma by interfering with the binding of PAI-I to vitronectin as shown in the following scheme,
• PAI-I decreases binding of trabecular meshwork (TM) cell surface adhesion receptors (integrins) to vitronectin, an extracellular matrix component.
• TM trabecular meshwork
• integrins cell surface adhesion receptors
• Agents that alter PAI-I 's ability to inhibit tissue plasminogen activator (tPA) and/or urokinase plasminogen activator (uPA) may modulate PAI-I binding as well.
• Such agents include, but are not limited to, ZK4044 (Liang et al., Characterization of a small molecule PAI-I inhibitor, ZK4044, Thromb Res., 2005, Vol. 115(4):341-50)), PAI-039 (tiplaxtinin) (Weisberg et al., Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor- 1 attenuates angiotensin II/salt-induced aortic remodeling.
• T-686 Murakami et al., Protective effect of T-686, an inhibitor of plasminogen activator inhibitor-1 production, against the lethal effect of lipopolysaccharide in mice. Jpn J Pharmacol., 1997 Nov, Vol. 75(3):291-4); Ohtani et al., T-686, a novel inhibitor of plasminogen activator inhibitor- 1, inhibits thrombosis without impairment of hemostasis in rats. Eur J Pharmacol., 1997 JuI 9, Vol.
• T-686 A new butadiene derivative, T-686, inhibits plasminogen activator inhibitor type-1 production in vitro by cultured human vascular endothelial cells and development of atherosclerotic lesions in vivo in rabbits.
• PAI-I inhibitors such as those taught by Ye (Ye et al., Synthesis and biological evaluation of piperazine-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-I). Bioorg Med Chem Lett., 2004 Feb 9, Vol. 14(3):761-5; Ye et al., Synthesis and biological evaluation of menthol-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-I). Bioorg Med Chem Lett., 2003 Oct 6, Vol. 13(19):3361-5) and antibody-based inhibitors such as those taught by Verbeke (Verbeke et al., Cloning and paratope analysis of an antibody fragment, a rational approach for the design of a PAI-I inhibitor.
• PAI-I binding modulators may comprise PAI-I peptidomimetics.
• the PAI-I -binding modulators of the present invention can be incorporated into various types of ophthalmic formulations for delivery.
• the compounds may be delivered directly to the eye (for example: topical ocular drops or ointments; slow release devices such as pharmaceutical drug delivery sponges implanted in the cul-de- sac or implanted adjacent to the sclera or within the eye; periocular, conjunctival, sub- tenons, intracameral, intravitreal, or intracanalicular injections) or systemically (for example: orally, intravenous, subcutaneous or intramuscular injections; parenteral, dermal or nasal delivery) using techniques well known by those of ordinary skill in the art. It is further contemplated that the PAI-I -binding modulators of the invention may be formulated in intraocular inserts or implantable devices.
• the PAI-I -binding modulators disclosed herein are preferably incorporated into topical ophthalmic formulations for delivery to the eye.
• the compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
• Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
• the ophthalmic solution may contain an agent to increase viscosity such as hydroxymethylcellulose, hydroxy ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
• Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
• the active ingredient is combined with a preservative in an appropriate vehicle such as mineral oil, liquid lanolin, or white petrolatum.
• Sterile ophthalmic gel formulations may be prepared by suspending the compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
• PAI-I -binding modulators are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8.
• the compounds are contained in the topical suspensions or solutions in amounts sufficient to lower IOP in patients experiencing elevated IOP and/or maintaining normal IOP levels in glaucoma patients. Such amounts are referred to herein as "an amount effective to control IOP," or more simply “an effective amount.”
• the compounds will normally be contained in these formulations in an amount 0.01 to 5 percent by weight/volume (“w/v %”), but preferably in an amount of 0.25 to 2 w/v %.
• w/v % percent by weight/volume
• the PAI-I -binding modulators may also be used in combination with other elevated IOP or glaucoma treatment agents, such as, but not limited to, rho kinase inhibitors, ⁇ -blockers, prostaglandin analogs, carbonic anhydrase inhibitors, ⁇ 2 agonists, miotics, serotonergic agonists and neuroprotectants.
• elevated IOP or glaucoma treatment agents such as, but not limited to, rho kinase inhibitors, ⁇ -blockers, prostaglandin analogs, carbonic anhydrase inhibitors, ⁇ 2 agonists, miotics, serotonergic agonists and neuroprotectants.
• PAI-I -binding modulator encompasses such modulators as well as their pharmaceutically-acceptable salts.
• a pharmaceutically acceptable salt of a PAI-I -binding modulator is a salt that retains PAI-I -binding modulatory activity and is acceptable by the human body. Salts may be acid or base salts since agents herein may have amino or carboxy substituents.
• a salt may be formed with an acid such as acetic acid, benzoic acid, cinnamic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, phosphoric acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and the like.
• a salt may be formed with a base such as a primary, secondary, or tertiary amine, aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, and the like.
• PAI-I binding modulators can be selected using binding assays or functional assays that can also be used to determine their biological activity. Such assays can be developed by those of skill in the art using previously described methods. Other assays are or can be derived from data presented infra in the Examples. For example, the TM cell migration assay later described can be used where a putative PAI-I binding modulator is added as a test agent.
• PAI-I -binding modulators to safely lower IOP may be evaluated in certain embodiments by means of in vivo assays using New Zealand albino rabbits and/or Cynomolgus monkeys.
• Both eyes of New Zealand albino rabbits are topically dosed with one 30 ⁇ L aliquot of a test compound in a vehicle. Animals are monitored continuously for 0.5 hr post-dose and then every 0.5 hours through 2 hours or until effects are no longer evident.
• Intraocular pressure is determined with a Mentor Classic 30 pneumatonometer after light corneal anesthesia with 0.1% proparacaine. Eyes are rinsed with one or two drops of saline after each measurement. After a baseline IOP measurement, test compound is instilled in one 30 ⁇ L aliquot to one or both eye of each animal or compound to one eye and vehicle to the contralateral eye. Subsequent IOP measurements are taken at 0.5, 1, 2, 3, 4, and 5 hours.
• Intraocular pressure is determined with an Alcon pneumatonometer after light corneal anesthesia with 0.1% proparacaine as previously described (Sharif et al, J. Ocular Pharmacol. Ther., 2001, Vol. 17:305-317; May et al, J. Pharmacol. Exp. Ther., 2003, Vol. 306:301-309). Eyes are rinsed with one or two drops of saline after each measurement. After a baseline IOP measurement, test compound is instilled in one or two 30 ⁇ L aliquots to the selected eyes of cynomolgus monkeys. Subsequent IOP measurements are taken at 1, 3, and 6 hours. Right eyes of all animals had undergone laser trabeculoplasty to induce ocular hypertension. All left eyes are normal and thus have normal IOP.
• FIGURE 1 presents the results of experiments showing that TGF ⁇ 2 increases the PAI-I content in trabecular meshwork cell cultures (GTM-3).
• PAI-I mediated effects may contribute to the previously observed TGF ⁇ 2 -mediated accumulation of extracellular matrix materials in various tissues, including TM tissues.
• FIGURE 2 demonstrates that such TGF ⁇ 2-mediated PAI-I increases are persistent in cell cultures treated with TGF ⁇ 2.
• TGF ⁇ 2 -treatment results in both concentration-dependent and time-dependent accumulation of PAI-I in TM cell supernatants (FIGURES 1 and 2).
• PAI-I levels increase gradually in response to TGF ⁇ 2, reaching a constant level at approximately 24 h post-treatment.
• FIGURE 3 presents experimental data demonstrating the ability of recombinant human PAI-I (2 h treatment) to decrease adhesion of cultured human TM cells to a vitronectin substrate; in that same model, adhesion was not affected by a mutant PAI-I which does not bind vitronectin (FIGURE 7).
• FIGURE 4 shows the effect of increasing concentrations of PAI-I on TM cell adhesion. The effect of PAI- 1 on adhesion was dose-dependent, with an estimated EC 50 of approximately 0.6 ⁇ M. Such interference with TM cell adhesion may thereby trigger accelerated TM cell loss such as that seen in glaucoma, particularly POAG.
• Detached TM cells may contribute to the obstruction of aqueous humor outflow, a process believed to lead to increased outflow resistance and elevated IOP. Loss of TM cells from the meshwork tissues may also lead to impaired debris clearance, as a result of reduced phagocytic capacity.
• cells that were treated with TGF ⁇ 2 for 2 hr did not experience measurable loss of adhesion when compared to controls.
• the lack of effect of short-term treatment with TGF ⁇ 2 is likely due to insufficient TGF ⁇ 2- mediated PAI-I induction during the 2 hr treatment period (vis. FIGURE 2).
• Responses of SV40-transformed (GTM-3) cells were highly similar to that of non- transformed (GTM730) cells.
• FIGURE 5 shows experimental data indicating that the wild type PAI-I- mediated loss of adhesion is transient, with adhesion levels returning to near-control levels after 24h.
• FIGURE 6 is a bar graph of experimental results showing the effect of wild-type PAI-I (1 ⁇ g/mL, 1 h) versus a stable, degradation-resistant PAI-I mutant (1 ⁇ g/mL, 1 h) on adhesion of GTM-3 and GTM730 cells to vitronectin substrate.
• the data demonstrate that wild-type PAI-I appears to degrade over time.
• the effect of PAI-I was therefore enhanced by use of a stable PAI-I mutant (mixture of the K154T, Q139L, M354I, and H150H mutations) which is more degradation-resistant than the wild-type protein.
• FIGURE 7 is a bar graph of experimental results showing the effect of wild- type PAI-I (1 ⁇ g/mL, 2 h) versus a non- vitronectin binding PAI-I mutant (1 ⁇ g/mL, 2 h) on adhesion of GTM-3 cells to vitronectin substrate.
• the mutant PAI-I which does not bind vitronectin yet is known to be otherwise functional, was without effect on TM cell adhesion to vitronectin substrate, while the wild-type vitronectin-binding PAI-I decreased adhesion to ca. 50% of control levels.
• FIGURE 8 is a graph of experimental results showing the concentration- dependent effect of wild-type PAI-I (4 h) on migration of GTM-3 cells. Wild-type PAI-I, at concentrations similar to that which reduce TM cell adhesion, induced migration of TM cells.
• Human TM cell culture Human TM cells were isolated from post-mortem human donor tissue, characterized, and cultured as previously described. Generation and characterization of the transformed (GTM-3) cell line was also as previously described (Pang et al. Preliminary characterization of a transformed cell strain derived from human trabecular meshwork. Curr. Eye Res. , 1994, Vol. 13:51 -63.)
• PAI-I ELISA 24-well plates of TM cell cultures were serum-deprived for 24 h followed by an additional 24 h (or as indicated) incubation with TGF ⁇ 2 in a serum- free medium. Aliquots of supernatants from the treated cultures were quantified for secreted PAI-I content by means of human PAI-I ELISA kit (American Diagnostica).
• TM cell adhesion was determined by means of InnoCyte ECM Cell Adhesion Assay (Calbiochem). TM cells (20,000/well; serum-free medium) were plated onto a vitronectin-coated 96-well plate. Test agents were then added, followed by incubation in a cell culture incubator for the times indicated. Nonadherent cells were then removed by decantation and gentle wash of the wells with PBS. Relative cell attachment was determined by means of fluorescent dye (calcein- AM) uptake.
• TM cell migration Migration of TM cells was assessed using InnoCyte Cell Migration Assay (Calbiochem). TM cells (50,000/well; serum-free medium) were plated into the upper well assembly of the migration chamber supplied with the kits. Lower wells were filled with solutions of the test agents and the chamber was then incubated in a cell culture incubator. After 4 h, the upper well assembly was removed and supernatants were gently decanted to remove unattached cells. The upper well assembly was then placed into a fresh lower plate containing a mixture of detachment buffer and calcein-AM. 60 minutes later, aliquots from each lower well were transferred to a fresh, black 96 well plate and relative fluorescence determined.

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