MXPA02004786A - Neurophilin ligands for treating ocular conditions - Google Patents

Abstract

The use of neurophilin ligands for treating glaucoma and lowering IOP is disclosed.

Description

LIGANDOS DE NEUROFILINA TO TREAT EYE CONDITIONS The present invention relates to the use of neurophilin ligands to prevent or reduce the velocity of visual field loss and to treat ocular hypertension associated with glaucoma.

BACKGROUND OF THE INVENTION Glaucomas are a heterogeneous group of optic neuropathies characterized by the formation of cup-shaped depressions of the head of the optic nerve, thinning of the fiber layer of the retinal nerve, and specific changes in visual fields. Elevated intraocular pressure (IOP) is a very important risk factor for the development of the most common forms of glaucoma (Sommer A., et al., "Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans," Arch. Ophthalmol., 109: 1090-1095 (1991) It is considered that elevated IOP is caused by the increased deposition of extracellular matrix material by cells of the trabecular network which fill the flow paths in the network trabecular or through a decrease in the synthesis, release and activation of matrix metalloproteinases through the cells of the trabecular meshwork or both.The result is that the trabecular meshwork is obstructed and can not perform one of its most important functions, which is serve as an access door for aqueous humor flow from the anterior chamber of the eye towards the Schlemm canal. When the flow of aqueous humor out of the eye through the trabecular meshwork decreases, the IOP rises. Due to the association between elevated IOP and glaucomatous visual field loss, glaucoma has traditionally been treated by decreasing IOP medically (Sugrue, MF, "New approaches to antiglaucoma therapy", J. Med. Chem., 40.2793-2809 ( 1997)), and / or by laser trabeculectomy, and / or surgically (Quigley, HA "Open-angle glaucoma", New England J. Med. 328: 1097-1106 (1993).) Laser trabeculectomy is frequently used in effective way to lower elevated IOP, however, the effects of laser trabeculectomy are rarely permanent.Laser treatment of the trabecular meshwork results in a dramatic increase in cell division in a population of cells considered to serve as stem cells of The trabecular network This leads to repopulation of the trabecular network (Acott, TS, et al. "Trabecular repopulation by anterior trabecular meshwork cells after laser trabeculectomy", Am. J. of Ophthalmol, 107.1-3 1989)). Laser treatment also induces an increase in the expression of matrix metalloproteinases in the trabecular network (Parshley DE et al., "Laser trabeculectomy induces stromelysin expression by trabecular juxtacanalicular cells" Invest. Ophthalmol. Vis. Sc / '. 37: 795 -804 (1996), Bradley, JD et al., "Effects of matrix metalloproteinase activity on outflow in perused human organ culture", Invest. Ophthalmol, Vis. Sci., 39: 2649-2658 (1998)). HE considers that this increase raises the rate of extracellular matrix degradation resulting in a decrease in flow resistance. High IOP does not always result in the appearance of visual field loss, and visual field loss can occur at IOP levels which are considered within the normal range. In this way, factors other than IOP can play a role in determining the occurrence of visual field loss. The degeneration of the retinal ganglion cells may be related to ischemia or a cascade of events that may have been initiated by the effects of IOP on the optic nerve which, once initiated, continues even if the IOP is normalized. Several methods have been directed to treat retinal ganglion cell degeneration including the use of polyamine antagonists (Kapin, MA USP 5,710,165: 1998), non-competitive inhibitors of the NMDA channel-receptor complex (Lipton, SA, USP 5,922,773: 1999). ), sodium channel blockers (Adorante, J.S., W098 / 43612), 2-α-dolin-2-yl (amino) quinoxalines (Wheeler, L.A. et al., USP 5,856,329), and EP2 receptor agonists (Woodward, D.F. USP 5,877,211). Immunophilins are a series of chaperone proteins which mediate the activity of immunosuppressant drugs such as FK506, rapamycin, and cyclosporin A (Pratt WB, et al, "Steroid receptor interactions with heat shock proteins and immunophilin chaperones," Endoc Rev, 18: 306-26 (1997)). Immunophilins are enriched in neurons throughout the peripheral and central nervous system, indicating that the Immunophilins may play a role in neural function. The discovery that dose-dependent FK-506 accelerates functional recovery from nerve damage, initiated an investigation to determine the mechanism of this function. The discovery that non-immunosuppressive analogues of FK-506 can also facilitate neuroregeneration, suggested that non-immunosuppressive immunophilin ligands (referred to herein as neurophilin ligands) may have therapeutic utility in a variety of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetic and peripheral neuropathies, and damage to the spinal cord (Hamilton, GS; Steiner, JP, "Immunophilins: Beyond Immunosuppression," J. Med. Chem., 41: 5119-5143). It was considered that the neurotrophic properties of immunophilin ligands (such as K-506) depend on their interaction with the 12-kDa FK-506 binding protein (FKBP-12). More recent studies have suggested that the protective effects of these compounds can be mediated by interaction with the immunophilin FKBP-52 (also known as FKBP-59 or heat shock protein 56) and possibly other related immunophilins (Gold, GG et al., "Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506" J Pharma8l Exp. Ther., 289: 1202-1210). The use of pipecolic acid derivatives having affinity with FKBP-type immunophilins to stimulate or promote growth or regeneration including neurological disorders of the eye has been described (Steiner, J.P. et al., WO 96/40140). It has also been described the use of N-glyoxyl-prolyl ester compounds having an affinity with FKBP-type immunophilin for the treatment of neurological disorders of the eye (Hamilton, G.S., et al., WO 96/40633).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the use of neurofilin ligands for treating glaucoma, decreasing and controlling IOP, and preventing loss of visual field associated with glaucoma in mammals.

DETAILED DESCRIPTION OF PREFERRED MODALITIES Neurophilin ligands are a class of compounds that treat glaucoma effectively by applying a protective effect on retinal ganglion cells and optic nerve head cells and by decreasing IOP by rejuvenating cells in the trabecular meshwork. Although the exact mechanism or mechanisms underlying the protective effect of neurofilin ligands are not fully understood, these compounds are effective in inhibiting neuronal degeneration and promoting neuroregeneration in models of animal neurotoxicity. In addition to reducing the rate of loss of retinal glangio cells and thus reducing the progressive visual field loss associated with glaucoma, it is believed that neurofilin ligands reduce elevated IOP to stimulate the cell function of the trabecular network. Neurophilin ligands have been shown to stimulate neurite outgrowth in PC12 cells, which, like cells in the trabecular network, are derived from stem cells in the neural crest. It is believed that neurophilin ligands will stimulate both proliferation and activation of trabecular network cells resulting in repopulation of the trabecular network and an increase in production or activation of matrix metalloproteinase which results in degradation of the waste. extracellular that obstructs the flow path. According to both aspects, the invention will preferably be used to treat patients who have primary open angle glaucoma, chronic closed angle glaucoma, pseudoexfoliation glaucoma, normal tension glaucoma, or other subtypes of glaucoma or ocular hypertension. Administration of the drug is achieved through routes including but not limited to topical ocular, periocular injection, intravitreal injection, or intravitreal implantation at a dose ranging from about 0.001 to about 2 mg / eye / day; systemic, including oral, transdermal, intravenous, transnasal, buccal or subcutaneous in concentrations of approximately 0.01 to approximately 10 mg / kg / day; or using an ocular implant, such as an intravitreal implant comprising approximately 0.2 to 100 mg. The neurofilin ligands of the present invention can be used alone (including a combination of more than one ligand of neurofilin) and in combination with other agents to treat glaucoma, such as IOP reducing drugs (eg, prostaglandin, beta-blockers, carbonic anhydrase inhibitors, muscarinics, sympathomimetics, alpha and serotonergic agonists) and / or neuroprotective agents (eg, blockers of calcium or sodium channels, glutamate antagonists, including NMDA antagonists, anti-apoptotic agents, adenosine reuptake inhibitors, nitric oxide synthase inhibitors, vasodilators, neurotrophic factor enhancers, neurotrophic factors (such as ciliary neurotrophic factor (CNTF), and basic fibroblast growth factor (bFGF, etc.). Preferred neurofilin ligands are those that have neurotrophic activity, but have little or no immunosuppressive activity, for example, one skilled in the art makes reference to the following patents and patent applications for their teaching of neu compounds Rotrophics lacking immunosuppressive activity: WO 99/14998 (Amgen, Method for Preventing and Treating hearing Loss using Sensorineurotrophic Compounds) and the references described therein, including, a series of picecholine derivatives that act as a neurophilin ligand (US 5,696,135); a series of proinin derivatives that act as neurophilin ligands (US 5,614,547); a series of N-sulfonylpipecolyl and prolyl derivatives that act as neurofilin ligands (US 5,721,256); a series of heterocyclic diesters and ketone that act as neurofilin ligands (US 5,796,378); a series of N-glyoxyl-prolyl esters that act as ligands of neurophysiin (US 5,795,908); a series of pipecolic acid derivatives that act as neurophysiin ligands (US 5,798,355); and a series of amide and heterocyclic ester derivatives that act as neurophyiine ligands (US 5,801, 187). Additional compounds that can be used in accordance with the present invention are described in US 5,840,736 (the use of a neurophysiin ligand in the presence of a neurotrophic factor to stimulate neurite overgrowth); US 5,654,332 (the use of a neurophysiin ligand in the presence of a nerve growth factor to stimulate neurite overgrowth); US 5,811, 434 (the use of a neurophysiin ligand in the presence of a nerve growth factor to stimulate neurite overgrowth); US 5,780,484 (the use of a piperidine derivative as a neurophysiin ligand in the presence of a nerve growth factor to stimulate neurite overgrowth); US 5846979 (the use of N-oxide heterocyclic esters, amides, tethers and ketones as neurophyiine ligands). Christner, C. et al. describe a series of cycloheximide derivatives as neurophysiin ligands with neuroregenerative properties ("Synthesis and Cytotoxic Evaluation of Cydoheximide Derivatives as Potential Inhibitors of FKBP12 with Neuroregenerative Properties", J. Medicinal Chem. 42: 3614-22, 1999) which can be use according to the methods of this invention.

A class of preferred compounds is described in the aforementioned patent US 5,840,736. Especially preferred is (S) -N-benzyl-3- (4-phenophenyl) -2- (methyl- (2-oxo-2- (3I4,5-trimethoxyphenyl) acetyl) amino) -N- (3-pyridinyl-). -) 1- (2- (pyridinyl-4-yl) -ethyl) propyl) propionamide (Timcodar). Another class of preferred compounds is described in the aforementioned patent US 5,614,547. Especially preferred is 1- (3,3-dimethyl-1,2-dioxopentH) - (1 -) - proline 3- (3-pyridinyl) propyl ester (GPI-1046).

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a neurophilin ligand that does not have immunosuppressive activity, for the preparation of a medicine to treat a mammal suffering from glaucoma.

2. The use as claimed in claim 1, wherein the neurofilin ligand is selected from the group consisting of (S) -N-benzyl-3- (4-dorophenyl) -2- (methyl- ( 2 ^ xo-2 (3,415-trimethoxy-phenyl) a8thyl) amino ^ N ^ 3 (pyridinyl-4-yl-) 1- (2- (pyridinyl-4-yl) -ethyl) propyl) propionamide and ester 1- (3,3-dimethyl-, 2-dioxopentyl) - (L) -propyne 3- (3-pyridinyl) propyl.

3. - The use of a neurophilin ligand that does not have immunosuppressive activity, for the preparation of a drug to reduce IOP in a mammal suffering from IOP.

4. The use as claimed in claim 3, wherein the neurofilin ligand is selected from the group consisting of (S) -N-benzyl-3- (4-dorophenyl) -2- (methyl- ( 2-oxo-2 (3,4,5-trimethoxy-phenyl) acetyl) amino) -N- (3- (pyridinyl-4-yl-) 1- (2- (pyridinyl-4-yl) -ethyl) propyl ) proponamide and 1- (3,3-dimethyl-1,2-dioxopentyl) - (L) -proline 3- (3-pyridinyl) propyl ester.

5. - The use of a neurofinila ligand that does not have immunosuppressive activity, for the elaboration of a medication to avoid the loss of visual field associated with glaucoma.

6. - The use as claimed in claim 5, wherein the neurofilin ligand is selected from the group consisting of (S) -N-bendl-3- (4-dorophenyl) -2- (methyl- (2) xo-2 (3,4,5-trimethoxy-phenyl) acetyl) amino) -N- (3- (pyridinyl-4-yl-) 1- (2- (pyridinyl-4-yl) -ethyl) propyl) propionamide and 1- (3,3-dimethyl-1,2-d-oxopentyl) - (L) -proline 3- (3-pyridinyl) propyl ester.

7. - The use of a neurofinila ligand that does not have immunosuppressive activity, for the elaboration of a medicine to reduce IOP and provide neuroprotection in a mammal suffering from elevated IOP.

8. The use as claimed in claim 7, wherein the neurofilin ligand is selected from the group consisting of (S) -N-bendl-3- (4-dorophenyl) -2- (methyl- ( 2-oxo-2 (3,4,5-trimethoxy-phenyl) -acetyl) amino) -N- (3 (pyridinyl-4-yl-) 1- (2- (pyridin-4-yl) -ethyl) propyl) propionamide and 1- (3,3-dimethyl-1,2-dioxopentyl) - (L) -proline 3- (3-pyridinyl) propyl ester.