MX2008007845A - Control of intraocular pressure using alk5 modulation agents - Google Patents
Control of intraocular pressure using alk5 modulation agentsInfo
- Publication number
- MX2008007845A MX2008007845A MXMX/A/2008/007845A MX2008007845A MX2008007845A MX 2008007845 A MX2008007845 A MX 2008007845A MX 2008007845 A MX2008007845 A MX 2008007845A MX 2008007845 A MX2008007845 A MX 2008007845A
- Authority
- MX
- Mexico
- Prior art keywords
- pyrazol
- quinoline
- methylpyridin
- triazol
- pyridin
- Prior art date
Links
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Abstract
An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure comprising an effective amount of a selective modulator of ALK5 receptor activity is disclosed. Also disclosed is a method of treating glaucoma and controlling intraocular pressure comprising applying a therapeutically effective amount of a pharmaceutical composition comprising a selective modulator of ALK5 receptor activity to an affected eye of a patient.
Description
INTRAOCULAR PRESSURE CONTROL USING KINASE MODULATION AGENTS 5 SIMILAR TO ACTIVINE RECEPTOR
This application claims priority under 35 U.S.C. §119 to the provisional patent application of the United States No. 60/751, 130, filed on December 16, 2006, the entire contents of which are incorporated by reference here.
TECHNICAL FIELD OF THE INVENTION
The present invention relates in general to treatments for glaucoma and more specifically to agents that selectively modulate the activity of kinase 5 similar to activin receptor (ALK5, or TGF-β type 1 receptor) thereby decreasing intraocular pressure as that associated with glaucoma.
BACKGROUND OF THE INVENTION
Glaucoma eye disease is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The various morphologically or functionally distinct types of glaucoma are typically characterized by an undesirable elevation of intraocular pressure (IOP), which is considered to be related to the course
pathological of the disease. Elevated IOP has been continuously associated with progressive deterioration of the retina and loss of visual function. In some cases, ocular hypertension, a condition in which the IOP is elevated, can occur without apparent loss of visual function. However, patients with ocular hypertension are considered to be at higher risk of eventually developing the visual loss associated with glaucoma. Therefore, lowering the IOP may be an objective for the treatment of patients with glaucoma and for patients with ocular hypertension to reduce the potential of, or severity of, glaucomatous retinopathies. Unfortunately, many people do not respond well when treated with existing glaucoma therapies. Patients who are known as patients with normotension or low tension glaucoma have a relatively low IOP and nevertheless present glaucomatous visual field loss. These patients may benefit from agents that decrease and control IOP because glaucoma that is detected early and treated promptly can reduce or decrease the loss of visual function. Conventional therapeutic agents that have proven to be effective for IOP reduction include agents that decrease the production of aqueous humor and agents that increase the ease of outflow. Such agents are generally administered by one of two routes; topically by direct application to the eye or orally. However, many of these agents have effects
associated side effects that may make them undesirable as ocular therapeutic agents. The beta-growth factor (TGF-β) family of cytosines includes multifunctional proteins that regulate the production of a wide variety of gene products and thereby control a wide variety of cellular processes. For example, members of the TGF-β family are involved in inflammation, wound healing, extracellular matrix accumulation, bone formation, tissue development, cell differentiation and tumor progression, among others. [Barnard et al., Biochim Biohys Acta. 1990; Vol. 1032: 79-87; Sport et al., J. Cell Biol., 1992; Vol. 119 *: 107-1021; Yinggling et al., Nature Reviews, Vol. 3: 1011-1022; Janssens et al., Endocr Rev., 2005; (electronic publication before printing)]. Three isoforms of mammals have been identified to date: TGF-β1, TGF-β2, and TGF-β3, and these isoforms are structurally similar despite being encoded by different genes [Massague J., Annu Rev Cell Biol., 1990; Vol. 6: 597-641] In aqueous humor (AH) collected from human eyes affected by primary open angle glaucoma (POAG), one of the most common forms of glaucoma in Western patients, several groups have reported significantly higher levels compared to normal eyes of the TGF-ß2 isoform. [Tripathi et al., Exp Eye Res., 1994; Vol. 59: 723-727; Inatani et al., Graefes Arch Clin Exp Ophthalmol., 2001; Vol. 239: 109-113; Picht et al., Graefes Arch Clin Exp Ophthalmol., 2001; Vol. 239: 199-207; Ochiai et al., Jpn JOphthalmol., 2002; Vol. 46: 249-253; Ozcan et al., Int Ophthalmol., 2004; Vol.
: 19-22]. The TGF-β2 isoform is also reported to increase the production of extracellular matrix (ECM). [Kottler et al., Exp eye Res., 2005; Vol. 80: 121-134]. In POAG, a disproportionate enlargement of ECM in the trabecular network (TM) of the eye is thought to impart greater resistance to the outflow of AH, resulting in a higher IOP. [Rohen et al., Graefes Arch Klin Exp Ophthalmol., 1972; Vol. 183: 251-266; Lee et al., Trans Ophthalmol Soc UK., 1974; Vol. 94: 430-449]. A direct link may therefore exist between high levels of TGF-ß2 in AH and a high lOP.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is in part related to methods of treating glaucoma in human patients or other mammals. The present invention also relates to methods for lowering and controlling elevated or normal lOP in a human patient or other mammals. Modalities of the present invention control lOP and treat glaucoma by modulating the activity of the ALK5 receptor. In vitro, TGF-ß2 acts on ALK5 (TGF-ß receptor type 1) resulting in increased production of extracellular matrix (ECM) proteins in the trabecular (TM) network. Therefore, it is postulated that the increase induced by TGF-ß2 in the production of ECM in TM at the end results in a higher IOP in vivo. The down regulation of the effects of responses mediated by TGF-β2 thus represents a means
potential to decrease and / or control lOP and treat glaucoma. For example, inhibition of ALK5 activity would be expected to lead to a reduction in the accumulation of ECM mediated by TGF-β2. Accordingly, if a compound that selectively inhibits or modulates the ALK5 receptor is introduced into such a system, the undesirable effects of TGF-β2 on lOP can be reduced or improved. In addition, the isoforms of TGF-β 1, 2 and 3 belong to a family of cytosines that signal via transmembrane serine / threonine kinase receptors; other members of this superfamily include activins, inhibins, bone morphogenetic proteins, growth and differentiation factors and Mullerian inhibitory substance. The TGF-beta isoform receptors are grouped into two classes: kinase receptors similar to activin type 1 (ALK5 or ALK1) and type II receptors. TGF-β signaling is achieved by phosphorylation of type II receptor type I receptors, for example ALK5, in the presence of TGF-β. ALK5, in turn, phosphorylates the cytosolic proteins Smad2 and Smad3. Phosphorylated Smad2 and Smad3 proteins then form a complex with another Smad protein, Smad4. The resulting Smad protein subsequently translocates to the nucleus and drives gene transcription. As used herein, the terms "selective ALK5 modulator" or "selective modulator" thus refers to an agent, other than Smad inhibitory proteins (eg Smad6 and Smad7), which inhibits either the activation / phosphorylation of ALK5 itself or that inhibits the ability of ALK5 to
Activate / phosphorylate your target Smad proteins. Said agent preferably inhibits ALK5 receptors on other ALK-like receptors, such as ALK3, which modulate signaling by bone morphogenic proteins. Said agent also preferentially inhibits ALK5 receptors compared to type II receptors or other signaling kinases such as MAPK p38. For example, GW-6604 has been reported as a potent inhibitor of the phosphorylation of ALK5 (IC50 ~ μM), compared to the phosphorylation of TGF-ß and MAPK p38 type II receptors (IC50 of 10 μM and 9.5 μM, respectively) . Brit Pharmacol., 2005; Vol. 145: 166-177. Certain embodiments of the present invention comprise compositions or methods that include or utilize compounds capable of selective modulation of ALK5 receptor activity thereby modulating the intraocular pressure in the eye. The interaction of cytosines, such as TGF-β2, or other compounds with the ALK5 receptor may result in changes in the production of extracellular tint proteins in the trabecular network, thus modulating the intraocular pressure. By modulating the activity of the ALK5 receptor, the compounds according to certain embodiments of the present invention are consequently useful for decreasing and / or controlling the lOP associated with normal tension glaucoma, ocular hypertension and glaucoma, including primary open angle glaucoma. in humans and other warm-blooded animals. When used in such applications, the compounds can be formulated into pharmaceutical compositions suitable for topical delivery to the eye.
In yet another embodiment of the present invention, an in vitro method selects a selective modulator for ALK5 receptor activity. This selection can help with the selection of new compounds for the treatment of glaucoma and lOP control. The method comprises culturing trabecular network cells in an appropriate growth medium. The cultured cells are divided into replication and / or experimental and / or control groups to which are added control solutions or experimental solutions comprising a selective activity modulator of AI.K5. Protein levels related to extracellular matrix, such as fibronectin, plasminogen activator inhibitor I (PAI-1), collagens, fibrillin, vitronectin, laminin, thrombospondin I, proteoglycans or integrins, are then measured in each cell culture group. The cell matrix protein levels can then be compared between groups to determine the effect of experimental solutions comprising a modulus of a selective ALK5 activity. The brief description above describes in a general manner the characteristics and technical advantages of certain embodiments of the present invention. Additional features and technical advantages will be described in the detailed description of the invention that follows. Novel features that are believed to be characteristics of the invention will be better understood from the detailed description of the invention when any attached drawings are considered in connection. However, the figures provided here
they are intended to help illustrate the invention or help develop the understanding of the invention and are not intended to be definitions of the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
A more complete understanding of the present invention and the advantages of this can be gained in reference to the following description, taken in conjunction with the figures of the accompanying drawings in which the reference numbers indicate similar characteristics and in which: 1 is a graph of results showing the effects of TGF-β2 infused in the LOP of a prefused human anterior segment model compared to the control; Figure 2 is a graph of results showing the effects of an ALK5 inhibitor on fibronectin levels in a prefused human anterior segment model treated with TGF-β2 compared to the control; Figure 3 presents graphs showing measured levels of fibronectin and PAI-1 in TM cell cultures in vitro to which various concentrations of an ALK5 inhibitor have been added; and Figure 4 presents graphs showing measured levels of
C-peptide type I procollagen (PIP) in cell cultures TM in vitro.
DETAILED DESCRIPTION OF THE INVENTION
Certain embodiments of the present invention comprise compounds, compositions, or methods that include or utilize compounds capable of selective modulation of the activator of the ALK5 receptor, thus modulating the intraocular pressure in the eye. Specific representative compounds that have been found to possess ALK5 modulating activity are listed below. Preferred embodiments, the compounds for carrying out the method of the present invention comprise compounds 1 and 2, shown below. In other embodiments, one or more of the following compounds may be used
Certain compounds shown above may be references by a manufacturer designation. These include compound 1 (SB-431542), compound 2 (LY-364947), compound 3 (LY-550410), compound 4 (LY-580276), compound 5 (SB-504124), compound 12 (GW-6604) , compound 13 (A-83-01), compound 14 (SB-525334), and compound 15 (SC-68376). In addition to the above compounds, or in other embodiments, one or more of the following compounds listed in Groups I and II below may be used:
Group I: 4- (3- (6-methyl-pyridin-2-yl) -1 H -pyrazol-4-yl) -7-ethoxy quinoline; 4- (3-pyridin-2-yl-1 H-pyrazol-4-yl) -7-ethoxyquinoline; 7-fluoro-4- [3- (6-methyl-pyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-Bromopyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6- [n-butylamino) pyridin-2-yl] -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-chloro-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-trifluoromethyl-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinolin; 7-methyl-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-methoxy-4- [3-1 H -pyrazol-4-yl] -quinoline; 6-trifluoromethoxy-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (3-chlorophenyl) -1 H -pyrazol-4-yl] -quinoline; 6-butoxy-4- (3-pyridin-2-yl-1 H -pyrazol-4-yl) -quinoline; 6-sec-butyl-4- (3-pyridin-2-yl-1 H -pyrazol-4-yl) -quinoline; 5-methyl-3- (6-methylpyridin-2-yl) -4 - (- 4-fluorophenyl) -1 H-pyrazole; 4- (4-methoxyphenyl) -5-methyl-3- (6-methylpyridin-2-yl) -1 H-pyrazole; 4- [5-methyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-propylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 3-cyclopropyl-5-
pyridin-2-yl-4-quinolin-4-yl-pyrazole; 3- (3-trifluoromethylphenyl) -4-quinolin-4-yl-pyrazole; 1-benzyl-3- (2-pyridyl) -4- (4-quinolyl) pyrazole; 1- (4-phenylbutyl) -3- (2-pyridyl) -4- (4-quinolyl) pyrazole; 2- (3- (2-pyridyl) -4- (4-quinolyl) pyrazolyl) ethan-1-ol; 2- (3- (2-pyridyl) -4- (4-quinolyl) pyrazolyl) ethyl methylsulfonate; 4- [2- (3- (2-pyridyl) -3- (4-quinolyl) -pyrazolyl) ethyl] morpholine; phenyl [2- (3- (2-pyridyl) -4- (4-quinolyl) -pyrazolyl) ethyl] amine; 4- (4-pyridin-2-yl-1 H-pyrazol-3-yl) -quinoline; and 4- (3-pyridin-2-yl-1 H-pyrazol-4-yl) -quinoline.
Group II: 5- [5- (6-methylpyridin-2-yl) -1 H- [1,2,3] triazol-4-yl] -benzo [1, 2,5] thiadiazole; 5- [2-ethyl-5- (6-methylpyridin-2-yl) -2 H- [1, 2,3] triazol-4-yl] -benzo [l, 2,5] thiadiazole; 6- [5- (6-methylpyridin-2-yl) -1 H- [1,2,3] triazol-4-yl] - [1,2,4] triazolo [1, 5-a] pyridine; 2- [5- (2,3-dihydrobenzofuran-5-yl) -3H- [1, 2,3] triazol-4-yl] -6-methylpyridine; 2- [5- (2,3-dihydrobenzo [1-4] dioxin-6-yl) -2 H- [1,2] triazol-4-yl] -6-methylpyridine; l-methyl-6- [5- (6-methylpyridin-2-yl) -2H- [1, 2,3] triazol-4-yl] -1 H -benzimidazole; 6- (2-ethyl-5- (6-methylpyridin-2-yl) -2H- [1,2,3] triazol-4-yl) - [1,4] triazolo [1, 5] a] pyridine; 6- (2-methyl-5- (6-methylpyridin-2-yl) -2 H - [1,2,3] triazol-4-yl) - [1,4] triazolo [1, 5-a] ] pyridine; 2- [5- (4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine; 2- [5- (3-fluoro-4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine; and 2- [5- (3-chloro-4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine. From the collection of compounds described above, the following can be obtained from commercial sources: 1, commercially available with Sigma, P.O. Box 14508, St. Louis, MO, 63178-9916; 2, commercially
available with Matrix Scientific, P.O. Box 25067, Columbia, SC, 29224-5067; and 15, commercially available from G. Scientific, Inc., 6450 Lusk BIvd. Suite E102, San Diego, CA, 92121. The other compounds can be synthesized as described in references of origin as follows [format: number (s) of compound, reference to synthesis]: 3 and 4, Sawyer et al., Bioorganic and Medicinal Chemistry Letters, 2004; Vol. 14: 3581-3584; 5 and 14, WO 2001 / 062756A1; 6, WO 2004/026871; 7, Gellibert et al., Journal of Medicinal Chemistry, 2004; Vol.
47: 4494-4506; 8, WO 2004/021989; 9, WO 2004/026307; 10, WO 2000/012497; 11, WO 2004/147574; 16, Kim et al., Bioorganic and Medicinal Chemistry Letters, 2004; Vol. 12: 2013-2020; 12, WO 2002/066462; 13, Tojo et al., Cancer Science, 2005; Vol. 96: 791-800; 17-21, WO 2004/016606; 22, publication of patent application of the US. No. 2004/116474;
23 and 24, Sawyer et al., Journal of Medicinal Chemistry, 2003; Vol. 46: 3953-3956; Group I compounds, WO 2004/026302; and Group II Compounds, patent application publication of the U.S.A. No. US 2004/152738. The above representative compounds are not intended in any way to limit the scope of the invention. The scope of the invention comprises any agents that can be identified as having the ability to regulate, inhibit, or selectively modulate the activity of kinase 5 similar to the activite receptor (ALK5; or TGF-β type I receptor). Figure 1 is a graph showing the effect of infused TGF-β2 in a perfused human anterior segment model. All donor eyes used in this model were used in accordance with the provisions of the Helsinki declaration for research involving human tissue and were used 24 hours post-mortem. Donors were not known to have a history of glaucoma or other eye disorder. Human ocular perfusion organ culture was performed as described in the available literature [Tschumper et al., Curr Eye Res., 1990; Vol. 9: 363-369; Clark et al., Invest Ophthalmol Vis Sci., 1995; Vol. 36: 478-489; Pang et al., J. Glaucoma, 2000; Vol. 9: 468-479; Pang et al., Invest Ophthalmol Vis Sci., 2003; Vol. 44: 3502-3510]. Briefly, anterior segments were dissected and mounted in custom Plexiglas culture chambers, then perfused with Dulbecco's modified serum-free Eagle Medium. HE
monitored the lOP every 5 seconds and averaged every hour. The perfused tissue was allowed to equilibrate at 37 ° C and 5% C02 until a stable baseline LOP was achieved, typically 2-4 days; tissues with unstable lOP were discarded. Stable tissues were further perfused with medium containing the test compounds as indicated and changes in lOP were recorded. Eluate samples were collected daily for fibronectin ELISA and PAI-1 content. Tissues were fixed and evaluated for viability / morphology by light and electron microscopy at the end of each study. Unacceptable tissue data were excluded from the results. The criteria for "unacceptable" tissues included findings such as leftover remnants in the TM region, denudation of TM beams, loss of Schlemm channel cells and / or TM and ruptures or Schlemm channel collapse. The results shown in Figure 1 indicate that a perfused human anterior segment model infused with TGF-β2 at 5 ng / mL resulted in elevated lOP at 24 hours when compared to a control. The lOP of the model receiving the infusion TGF-ß2 was almost twice that of the control after 72 hours. As stated above, the introduction of compounds with selective modulating activity of ALK5 reduces or improves the undesirable effects of ECM production induced by TGF-β2. In Figure 2, experimental results showing lower levels of fibronectin in perfusates are presented from human anterior segments treated with TGF-β2 and compound 1, shown below,
compared to a perfused control model with only TGF-β2. Compound 1 completely antagonized the increase mediated by TGF-β2 in the content of the fibronectin perfusate.
1
Figure 3 shows graphs summarizing the results of a study using human cultured TM cells. The generation and characterization of the transformed cell line of GTM-3 has been previously described (Pang et al., Curr Eye Res., 1994; Vol. 13:51 -63). In summary, the maintenance growth medium consisted of Dulbecco's modified Eagle medium with Glutamax I (Gibco / BRL, Grand Island, NY) supplemented with 10% fetal bovine serum (Hyclone, Logan, UT) and 50 μg / mL gentamicin ( Gibco / BRL). For the assay, the cultures were trypsinized and seeded in 24-well plates (Corning Costar, Acton, MA) and allowed to grow until the monolayers reached approximately 90% confluence. The culture medium was then replaced with 0.25 ml of serum-free medium and antibiotic containing the appropriate test compounds. The cells were incubated 24 h at 5% CO2 and 37 ° C. Aliquots of culture supernatants were then assayed for fibronectin and / or PAI-1 content by ELISA.
The results of the study shown in FIG. 3 reveal a dose-dependent inhibition of TGF-.beta.2-mediated increase in fibronectin and PAI-1 content in supernatants of TM human celand cultures by modulators of ALK-5 1 and 2.
Figure 4 shows graphs summarizing measured levels of C-peptide (PIP) type 1 pro-collagen in human TM cell cultures. For this experiment, transformed GTM-3 cells (Pang et al., Curr Eye Res., 1994; Vol. 13: 51-63) were cultured in a culture medium consisting of Dulbecco's modified Eagle's medium with Glutamax I (Gibco / BRL, Grand Island, NY) supplemented with 10% fetal bovine serum (Hyclone, Logan, UT) and 50 μg / mL gentamicin (Gibco / BRL). For the assay, the cultures were enzymatically dissociated (TrypLE Express, Gibco / lnvitrogen) and seeded in 24-well plates (Corning Costar, Acton, MA) and allowed to grow until the monolayers reached approximately 90-95% confluence. The culture medium was then replaced with 0.25 ml of serum-free medium and antibiotic containing the appropriate test compounds. The cells were incubated 24 h at 5% CO2 and 37 ° C. Aliquots of culture supernatants are
then assayed by ELISA equipment for C-type I procollagen peptide (TaKaRa Bio, Shiga, Japan). The collagens are synthesized as pro-collagens, most of which contain additional polypeptide sequences called "propeptides". The propeptides are located at the N- and C-terminal ends of the molecules. These propeptides help facilitate the formation of the triple-matched spiral structure of collagen from procollagen within the endoplasmic reticulum. The propeptide portions are then cleaved from the triple helical collagen molecules with the secretion - thus the concentration of free propeptide, such as PIP, can be used to relate changes in the amount of the collagen that is synthesized by the cells. The results of both study replicates showed that PIP levels are elevated to a large extent in cultures treated with TGF-β2 compared to the vehicle. However, when the cultures are treated with TGF-β2 and compound 1 modulator of ALK5, this PIP elevation dependent on TGF-β2 is eliminated. Thus, the results of the study shown in FIG. 4 demonstrate the inhibition of increases mediated by TGF-.beta.2 in PIP levels by the compound 1 modulator of ALK5. Since PIP levels are directly linked to the production of collagen, an ALK5 modulator, such as compound 1, appears to decrease collagen production and consequently should inhibit the production of global ECM protein in TM. Table 1, shown below, summarizes the results of a study that measures the effect of TGF-β2 on related protein levels
with ECM (fibronectin, PAI-1) in cultured TM cells of several strains. TGF-ß2 was present in the cultures at a concentration of 5 ng / mL, and protein levels (mean ± s.e.m.) were measured after 24 hours. The results of the table indicate that TGF-β2 increases the production of fibronectin and PAI-1 in a variety of human TM cell cultures
TABLE 1 Effects of TGF-ß2 on HTM cell secretion of fibonectin and PAI-1
By virtue of the results summarized above, an appropriate conclusion is that IOP levels can be effectively controlled and glaucoma treated with compositions and methods comprising and using compounds with a modulating effect on the activity of the ALK5 receptor.
The selective modulator compounds used in accordance with certain embodiments of the present invention can be incorporated into various types of ophthalmic formulations for delivery. The compounds can be delivered directly to the eye (eg, topical eye drops or ointments, slow-release devices at the bottom of the sac or implanted adjacent to the sclera or within the eye, periocular, conjunctival, sub-tenons, intracameral, intravitreal, or injections). intracanalicular). In certain embodiments, the compounds may be delivered systemically (e.g., orally, intravenous, subcutaneous or intramuscular injections, parenterally, dermal or nasal delivery) using techniques well known to those skilled in the art. It is further contemplated that the agents of the invention may be formulated into intraocular inserts or implant devices. Preferred embodiments, selective modulator compounds according to the present invention are incorporated into topical ophthalmic formulations to be delivered to the eye. The compounds can be combined with ophthalmologically acceptable preservatives, surfactants, viscosity improvers, penetration enhancers, pH regulators, sodium chloride and / or water to form an aqueous, sterile ophthalmic suspension or solution. Formulations in ophthalmic solution can be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous pH regulator. In addition, the ophthalmic solution may include an ophthalmologically acceptable surfactant to help dissolve the
compound. The ophthalmic solution may also contain an agent to increase the viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone or the like, to improve the retention of the formulation in the conjunctival sac. Also gelling agents can be used including, without restriction, gellan and xanthan gum. To prepare sterile ophthalmic ointment formulations, a selective modulator compound is combined with an observer in an appropriate vehicle, such as mineral oil, liquid lanolin or white petrolatum. Sterile ophthalmic gel formulations can be prepared by suspending the compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to published formulations for analogous ophthalmic preparations; Conservatives and tonicity agents can be incorporated. In certain embodiments, the selective modulator compounds are preferably formulated as topical ophthalmic suspensions or solutions with a pH of about 4 to 8. The compounds will normally be contained in these formulations in an amount of 0.01 to 5% w / v ( "% p / v"), but preferably in an amount of 0.25 to 2% w / v. A typical dosage regimen will comprise the administration of one or two drops of these formulations to the surface of the eye 1 to 4 times per day, in accordance with the discretion of a skilled physician.
Selective modulator compounds can also be used in combination with other agents to treat glaucoma, such as, but not limited to, β-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, a2 agonists, miotics, and neuroprotectants. Certain embodiments of the present invention comprise the in vitro method of selection of selective modulators of ALK5 receptor activity for treatment of glaucoma and control of lOP. In general, these embodiments comprise culturing a plurality of TM cells in a suitable medium. The TM cells can be cultured in certain embodiments according to the TM culture method described in the description for Figure 3. An ALK5 activity selective modulator is added to a first population of cultured cells. In these modalities, a control population that does not have a selective modulator is also prepared. Then, levels of an extra cellular matrix protein, such as fibronectin or PAI-1, are measured for each cell culture population in the presence and absence of TGF-β2. Any extracellular matrix proteins can be measured in embodiments of the present invention. The levels measured in a first population and a control population are then compared. Said comparison can be used to select selective modulators for ALK5 receptor activity and to determine if such selective modulators will be useful for glaucoma treatment and lOP control.
Shown below are several examples of pharmaceutical compositions according to embodiments of the present invention. The following examples are provided to illustrate the utility of the present invention but should not be construed as implying any limitation to the claims.
EXAMPLE 1
EXAMPLE 2
EXAMPLE 3
EXAMPLE 4
The present invention and its embodiments have been described in detail. However, the scope of the present invention is not intended to be limited by the particular modalities of any process, manufacture, composition of matter, compounds, means, methods and / or steps described in the specification. Various modifications, substitutions and variations can be made to the described material without deviating from the essence and / or essential features of the present invention. Consequently, one aspect in the art will readily appreciate from the description that you are
Last modifications, substitutions and / or variations that perform substantially the same function or achieve substantially the same result as the embodiments described herein may be used in accordance with such related embodiments of the present invention. Thus, the following claims are intended to encompass within their scope modifications, substitutions and variations to processes, manufactures, compositions of matter, compounds, means, methods and / or steps described herein.
Claims (6)
1. An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and intraocular pressure control comprising: a selective modulator of ALK5 receptor activity.
2. The composition according to claim 1, further characterized in that said selective modulator is selected from the group consisting of: 4- (3- (6-methyl-pyridin-2-yl) -1 H -pyrazol-4-yl) -7-ethoxy quinoline; 4- (3-pyridin-2-yl-1 H-pyrazol-4-yl) -7-ethoxy-quinoline; 7-fluoro-4- [3- (6-methyl-pyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-Bromopyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6- [n-butylamino) pyridin-2-yl] -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-chloro-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-trifluoromethyl-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 7-methyl-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 6-methoxy-4- [3-1 H -pyrazol-4-yl] -quinoline; 6-trifluoromethoxy-4- [3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (3-chlorophenyl) -1 H -pyrazol-4-yl] -quinoline; 6-butoxy-4- (3-pyridin-2-yl-1 H -pyrazol-4-yl) -quinoline; 6-sec-butyl-4- (3-pyridin-2-yl-1 H -pyrazol-4-yl) -quinoline; 5-methyl-3- (6-methylpyridin-2-yl) -4 - (- 4-fluorophenyl) -1 H-pyrazole; 4- (4-methoxyphenyl) -5-methyl-3- (6-methylpyridin-2-yl) -1 H-pyrazole; 4- [5-methyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 4- [3- (6-propylpyridin-2-yl) -1 H -pyrazol-4-yl] -quinoline; 3-cyclopropyl-5-pyridin-2-yl-4-quinolin-4-yl-pyrazole; 3- (3-trifluoromethylphenyl) -4-quinolin-4-yl-pyrazole; 1-benzyl-3- (2-pyridyl) -4- (4-quinolyl) pyrazole; 1- (4-phenylbutyl) -3- (2-pyridyl) -4- (4-quinolyl) pyrazole; 2- (3- (2-pyridyl) -4- (4-quinyl) pyrazolyl) ethan-1-ol; 2- (3- (2-pyridyl) -4- (4-quinolyl) pyrazolyl) ethyl methylsulfonate; 4- [2- (3- (2-pyridyl) -3- (4-quinolyl) -pyrazolyl) ethyl] morpholine; phenyl [2- (3- (2-pyridyl) -4- (4-quinolyl) -pyrazolyl) ethyl] amine; 4- (4-pyridin-2-yl-1 H-pyrazol-3-yl) -quinoline; and 4- (3-pyridin-2-yl-1 H-pyrazol-4-yl) -quinoline; 5- [5- (6-methylpyridin-2-yl) -1 H- [1,2] triazol-4-yl] -benzo [1, 2,5] thiadiazole; 5- [2-ethyl-5- (6-methylpyridin-2-yl) -2H- [1, 2,3] triazol-4-yl] -benzo [l, 2,5] thiadiazole; 6- [5- (6-methylpyridin-2-yl) -1 H- [1,2,3] triazol-4-yl] - [1,2,4] triazolo [1, 5-a] pyridine; 2- [5- (2,3-dihydrobenzofuran-5-yl) -3H- [1, 2,3] triazol-4-yl] -6-methylpyridine; 2- [5- (2,3- dihydrobenzo [1-4] dioxin-6-yl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine; l-methyl-6- [5- (6-methylpyridin-2-yl) -2H- [1, 2,3] triazol-4-yl] -1 H -benzimidazole; 6- (2-ethyl-5- (6-methylpyridin-2-yl) -2H- [1,2,3] triazol-4-yl) - [1,4] triazolo [1, 5-a] pyridine; 6- (2-methyl-5- (6-methylpyridin-2-yl) -2 H - [1,2,3] triazol-4-yl) - [1,4] triazolo [1, 5-a] ] pyridine; 2- [5- (4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine; 2- [5- (3-fluoro-4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine; and 2- [5- (3-chloro-4-methoxyphenyl) -2 H- [1, 2,3] triazol-4-yl] -6-methylpyridine.
3. The composition according to claim 1, further characterized in that it comprises a pharmaceutically acceptable salt of said selective modulator.
4. The composition according to claim 1, further characterized in that it also comprises a compound selected from the group consisting of: preservatives, surfactants, viscosity improvers, penetration enhancers, gelling agents, hydrophobic bases, vehicles, pH regulators , sodium chloride and water ophthalmologically acceptable.
5. The composition according to claim 1, further characterized in that it also comprises a glaucoma treatment agent.
6. The composition according to claim 5, further characterized in that said glaucoma treatment agent is selected from the group consisting of: beta-blockers, analogs of prostaglandin, carbonic anhydrase inhibitors, a2 agonists, miotics and neuroprotectors. 1 - The composition according to claim 1, further characterized in that said composition comprises from about 0.01 weight percent / volume to about 5 weight percent / volume of said compound. 8. The composition according to claim 1, further characterized in that said composition comprises from about 0.25 weight percent / volume to about 2 weight percent / volume of said compound. 9. The composition according to claim 1, further characterized in that said composition also comprises a preservative, tonicity agent, antioxidant, stabilizer, wetting agent, clarifying agent or a viscosity enhancing agent. 10. An in vitro method for selecting a selective modulator of ALK5 receptor activity for the treatment of glaucoma and intraocular pressure control comprising: culturing a plurality of trabecular network (TM) cells in an appropriate medium; adding said selective modulator to a first population of said TM cells; and comparing measured levels of a protein related to extracellular matrix in said first population and in a control population. 11. The method according to claim 10, further characterized in that said matrix-related protein Extracellular is selected from the group consisting of: fibronectin, plasminogen activator inhibitor (PAI-1), collagens, fibrillin, vitronectin, laminin, thrombospondin I, proteoglycans and integrins. 12. The use of a pharmaceutical composition comprising a selective modulator of ALK5 receptor activity for the manufacture of a medicament useful for treating glaucoma and controlling intraocular pressure in an affected eye of a patient. 13. The use as claimed in claim 12, wherein said composition is a composition of claim 2. 14. The use as claimed in claim 13, wherein said medicament is adapted to be administrable by a technique selected from the group consisting of: periocular injection, conjunctival injection, sub-tenon injection, intracameral injection, intravitreal injection, intracanalicular injection, implanting the delivery device in the cul-de-sac, implanting the supply device adjacent to the sclera, implanting the delivery device within the eye, oral administration, intravenous administration, subcutaneous administration, intramuscular administration, parenteral administration, dermal administration and nasal administration. 15. The use as claimed in claim 12, wherein said pharmaceutical composition comprises a preservative, tonicity agent, antioxidant, stabilizer, wetting agent, clarifying agent or a viscosity enhancing agent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/751,130 | 2005-12-16 |
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MX2008007845A true MX2008007845A (en) | 2008-09-02 |
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