Patent Grant
8647612
As we age, our lenses undergo physiological changes that make it more difficult to focus on near objects. That is why nearly everyone requires reading glasses, even as early as age 35-40. The ability of the eye to change focal power, also known as accommodative amplitude, decreases significantly with age. The accommodative amplitude is 20 diopters in children and young adults, but it decreases to 10 diopters by age 25 and to ≦1 diopter by age 60. The age-related inability to focus on near objects is called presbyopia. All of us will develop presbyopia and will require corrective lenses unless a new treatment is found.
Both presbyopia and cataract are age-related and may share common etiologies such as lens growth, oxidative stress, and/or disulfide bond formation.
There is a need for agents, compositions, and methods for combating ocular disease, including presbyopia and/or cataract.
In one embodiment, a method of treating presbyopia comprises administering an agent including at least two components independently selected from a sulfur atom, a selenium atom, and a sulfonic group. In one embodiment, at least one of the two components is selenium. The agent can be a five- or six-membered heterocycle or a non-cyclical compound.
In another embodiment, the agent has a formula of 6-A, 6-B, 6-C, 6-D, or 6-E. In another embodiment, the agent has the formula 6-A. In another embodiment, the agent has a formula 6-D or 5-E. In another embodiment, the agent has a formula 6-NC or 5-NC. In yet another embodiment, the agent has a formula 5-A or 5-B. In another embodiment, the agent has the formula NC.
Each of X and Y can be sulfur, selenium, or a sulfonic group. In one embodiment, X and Y are both sulfur. In another embodiment, one of X and Y is sulfur, and the other is sulfur or selenium.
Each R group is independently selected from the group consisting of: —H, —OH, —OAc, —OR, —SR, —CO2R, an electron withdrawing group, and a linear or branched C1-18 alkane or alkene optionally substituted by one or more substituents selected from the group consisting of ether, ester, carboxylic acid, phosphate, amide, and amine groups. In another embodiment, at least one R group is —OH or —OAc.
In yet another embodiment, at least one R group is a C2-10 alkane or C10-18 alkene. In another embodiment, at least one R group is —(CH2)2-10NH2. In another embodiment, at least one R group is —(CH2)2-10CO2H.
In one embodiment, the agent is one of the following or a derivative thereof: lipoic acid; cystine; 3,6-dihydro-1,2-dithiine; 3,4-dihydro-1,2-dithiine; 3-vinyl-[4H]-1,2-dithiine; diallyl disulfide; diallyl trisulfide; 3-prop-2-enylsulfinylsulfanylprop-1-ene; 1,2-dithiane; 6-((4R,5R)-4,5-dihydroxy-1,2-dithian-4-yl)hexanoate; (4R,5R)-5-hydroxy-1,2-dithian-4-yl acetate; (4R,5R)-1,2-dithian-4,5-diyl diacetate; or trans-4,5-dihydroxy-1,2-dithiane; or dithiothreitol.
In another embodiment, the agents are employed for pharmaceutical formulations and/or methods of treating ocular disease, e.g., presbyopia or cataract.
Agents, compositions, and methods are provided that can prevent, reduce, reverse, and/or slow the rate of lens growth, oxidative damage, and/or disulfide bond formation. These agents, compositions, and methods may thus effectively prevent or treat presbyopia and/or cataract.
The agents described herein are dithiol compounds or dithiol derivatives. The dithiol compounds and dithiol derivatives are referred collectively herein as agents. Dithiol compounds contain at least two sulfur atoms, preferably exactly two sulfur atoms, while dithiol derivatives include a selenium or sulfonic group in place of one or more sulfur atoms of a dithiol compound. Thus, in one embodiment, the agent has at least two components, each independently selected from a sulfur atom, a selenium atom, and a sulfonic group. In another embodiment, the agent has at least two components, each independently selected from a sulfur atom and a selenium atom. The agents can be on the backbone and/or the substituents of the compound.
The agents can be cyclical, e.g. a five- or six-membered heterocycle, or non-cyclical. Exemplary five-membered heterocycles (designated by Formula 5) include, but are not limited to:
Exemplary six-membered heterocycles (designated by Formula 6) include, but are not limited to:
Exemplary non-cyclical agents (designated by NC) include, but are not limited to:
The agents can be classified in various ways. For example, the agent can be encompassed by any one of the following classification groups:
5-A, 5-B, 6-A, 6-B, 6-C, 6-D, and 6-E: cyclical
5-NC, 6-NC, and NC: non-cyclical
5-A, 5-B, and 5-NC: 5-membered
5-A and 5-B: 5-membered cyclical
6-A, 6-B, 6-C, 6-D, 6-E, and 6-NC: 6-membered
6-A, 6-B, 6-C, 6-D, and 6-E: 6-membered cyclical
5-A and 5-NC: potential hydrogenation pair
6-A and 6-NC: potential hydrogenation pair
5-NC and 6-NC: potential hydrogenation products
5-A, 6-A, 6-D, and 6-E: adjacent thiols
5-A and 6-A: adjacent thiols, saturated ring
6-A, 6-D, and 6-E: adjacent thiols, 6-membered cyclical
5-B, 6-B, and 6-C: non-adjacent thiols
5-B and 6-B: 1,3 thiols
6-A, 6-B, and 6-C: dithanes
6-D and 6-E: dithiines
or the agents can be classified by any individual formula.
For each of the agents, X and Y are independently selected from a sulfur atom, a selenium atom, and a sulfonic group. Preferably, at least one of X and Y is sulfur. In one embodiment, X and Y are both sulfur. In another embodiment, one of X and Y is sulfur, and the other is sulfur or selenium. In yet another embodiment, one of X and Y is sulfur, and the other is selenium. In one embodiment, the agent is a seleno derivative where at least one of X and Y is selenium. Without being bound by theory, it is believed that the selenium atom advantageously helps to overcome redox potential.
Each R group is independently selected from —H, —OH, —OAc, —OR, —SR, —CO2R, an electron withdrawing group, and a linear or branched C1-18 alkane or alkene optionally substituted by one or more ether, ester, carboxylic acid, phosphate, amide, and/or amine groups. In another embodiment, each R group is independently —H, —OH, —OAc, —CO2CH3, or a linear C1-18 alkane or alkene optionally having a distal terminal that is —COOH, —NH2, —CO2CH3, or —CO2CH2CH3.
In one embodiment, various agents can be prepared by altering the placement of a particular R group. Any particular R group can be attached, for example, to a carbon adjacent to a thiol group (sulfur atom) or thiol derivative (e.g., selenium or sulfonic group). R1, R2, R7, R8, R9, R10, R11, R12, R13, and R14 represent such thiol-adjacent positions. In another embodiment, an R group can be attached to a carbon not adjacent to a thiol group or thiol derivative. R3, R4, R5, and R6 represent such non-adjacent positions. In yet another embodiment, an R group can be attached directly to a thiol group or thiol derivative. R15, R16, R17, and R18 represent such direct thiol attachments.
In one embodiment, one, two, or more R groups are —H. In some embodiments of Formula 5-NC and 6-NC, both of R15 and R16 are —H.
In one embodiment, one, two, or more R groups are —OH.
In another embodiment, one, two, or more R groups are —OAc. Without being bound by theory, the addition of an acetate ester (—OAc) is believed to improve corneal permeability, which is especially beneficial for the treatment of presbyopia.
In yet another embodiment, each R group is independently —H, —OH, —OAc, or —CH3. In another embodiment, one R group is a chain substituent, and the remaining R groups are independently —H, —OH, —OAc, or —CH3.
In one embodiment, the agent has the structure of Formula 6-A:
wherein each of R1, R2, R7, and R8 is —H; and
R3, R4, R5, and R6 are independently selected from —H, —OH, and —OAc.
In another embodiment, one, two, or more R groups are —CO2R. In another embodiment, one, two, or more R groups are —OR. In particular embodiments, the R of —CO2R or —OR is a lower alkyl group having 1-8 carbons. In one embodiment, —CO2R is —CO2CH3.
In one embodiment, the agent includes a C1-18 alkane or alkene, which are collectively referred to herein as chain substituents. The agent can be modified by altering the length of the chain substituent(s). Without being bound by theory, longer chains are believed to render the compound more hydrophobic, more lipid soluble, and thus more easily transported across the cell membrane. The length of the chain is limited by the lipid membrane width; a chain longer than the membrane width is likely to cause saponification. Shorter chains, on the other hand, and other similarly small substituents such as —OH and —CO2CH3, may be useful for preparing agents that are active in the cytosol and do not require membrane permeability. Substituent size and its concomitant effect on solubility also affect formulation considerations. For example, a hydrophobic drug may be more difficult to formulate as an administratable solution, but it may be more easily formulated for sustained release delivery systems.
In one embodiment, the agent includes a linear C1-18 alkane or alkene, which are collectively referred to herein as linear substituents. Without being bound by theory, linear substituents are more commonly found in natural compounds, so agents including linear substituents may be better tolerated by the body. However, branched substituents may also be used. The linear substituent can be, for example, attached to a carbon adjacent to a thiol group (sulfur atom) or thiol derivative (e.g., selenium or sulfonic group). In other words, one or more of R1, R2, R7, R8, R9, R10, R11, R12, R13, and R14 can be a linear substituent. In another embodiment, one or more of R3, R4, R5, and R6 can be a linear substituent.
In one embodiment, a chain substituent includes an ether, ester, carboxylic acid, phosphate, and/or amine group at the distal terminal of a chain. In one embodiment, the distal terminal is a carboxylic acid or an amine. In another embodiment, one, two, or more R groups are —(CH2)2-10CO2H or —(CH2)2-10NH2. Without being bound by theory, it is believed that carboxylic acid and amine terminals provide attachment points for natural amino acids to form peptide amide bonds. For example, the carboxylic acid terminal of exemplary agent lipoic acid is often covalently attached to the amine lysine side chain of the active mitochondrial enzyme. The mitochondrial functionality of lipoic acid is discussed in further detail below.
In another embodiment, the distal terminal of a chain substituent is an ester, e.g., methyl or ethyl ester. In one embodiment, one, two, or more R groups are —(CH2)2-10CO2CH3 or —(CH2)2-10CO2CH2CH3. Without being bound by theory, esterification is one way to modify the delivery of the pharmaceutical agent since the agent is inhibited from entering the cell until the ester is broken, e.g., by naturally occurring esterases. In this way, an esterified agent can serve as a prodrug that can be converted to an active form.
In one embodiment, the linear substituent is a linear C1-18, C2-12, C2-10, C2-8, C2-6, C4-6, C5-6, or C5 alkane. Exemplary agents including a linear alkane substituent are provided in the table below. The remaining undefined R groups are independently —H, —OH, —OAc, or —CH3.
Exemplary agent lipoic acid and some derivatives thereof include a linear alkane with a carboxylic acid terminal:
In one embodiment, the agent is lipoic acid (5-(1,2-dithiolan-3-yl)pentanoic acid), particularly alpha lipoic acid. In another embodiment, the agent is a lipoic acid derivative. Preferred lipoic acid derivatives do not interfere with the natural cellular mechanisms utilizing lipoic acid and/or dihydrolipoic acid. The agents described herein include those having relatively minor modifications to lipoic acid (e.g., altering chain length, replacing a sulfur atom with selenium) such that naturally occurring mitochondrial mechanisms can utilize either lipoic acid or the derivative. Agents having minor modifications may be relatively substitutable for lipoic acid and do not interfere with mitochondrial activity. Thus, in one embodiment, the agent functionally mimics lipoic acid in terms of redox activity and/or mitochondrial activity, but is not structurally identical to lipoic acid. Other agents include those having more major modifications to lipoic acid (e.g., altering chain placement). Such major modifications may render the agent unrecognizable to the mitochondria, thus avoiding interference with cellular mechanisms. In this way, both minor and major modifications can avoid mitochondrial interference. Mitochondrial interference, or the lack thereof, can be verified by in vitro testing according to methods known in the art such as, for example, a JC-1 Mitochondrial Membrane Potential Assay Kit (Cell Tech. Inc.). One of ordinary skill in the art could balance the strength of the reducing agent, which is believed to be responsible for the therapeutic effect, against mitochondrial interference, which might cause adverse effects. Exemplary lipoic acid derivatives include, but are not limited to: 5-(1,2-thiaselenolan-5-yl)pentanoic acid and 5-(1,2-thiaselenolan-3-yl)pentanoic acid.
In another embodiment, the linear substituent is a linear C1-18, C1-8, C5-15, C10-18, or C10-16, or C12-14 alkene. The alkene chain can have one, two, three, or more double bonds. Without being bound by theory, linear alkenes of relatively longer length, e.g., C10-18, particularly those including a carboxylic acid or ester group, may exhibit advantageous properties similar to a fatty acid group.
Alkenes, including those of shorter lengths, are also useful, especially for embodiments of Formula NC. For example, in one embodiment, each of R17 and R18 is independently selected from C2-8, C2-6, C3-6, C3-5, or C3 alkenes. In another embodiment of Formula NC, R17 and/or R18 is an —SC2-8 alkene.
A chain substituent can include more than one ether, ester, carboxylic acid, phosphate, or amine substituent. For example, one exemplary agent is cystine (3,3′-disulanedylbis(2-aminopropanoic acid)), which includes both carboxylic acid and amine substituents. In one embodiment, the agent is cystine or a derivative thereof such as the exemplary derivative shown below:
In another embodiment, R is an electron withdrawing group, which can decrease the pKa of the agent. Electron withdrawing groups include, but are not limited to: halogens (e.g., F, Cl), nitriles (CN), carboxylic acids (COOH), and carbonyls (CO).
In one embodiment, the agent is an allium oil antioxidant or a derivative thereof. Allium oil antioxidants are advantageously natural, nontoxic, and lipid soluble. Some have been studied as potential cytostatic agents for the treatment of atherlerosclerosis, cancer, etc. Without being bound be theory, the cytostatic properties may also provide advantageous efficacy in the context of ocular diseases caused by lens growth, including presbyopia and cataract.
One class of allium oil antioxidants is the dithiines. Exemplary dithiines include, but are not limited to:
Other allium oil antioxidants include, but are not limited to:
In another embodiment, the agent can be a dithiane or a derivative thereof. Without being bound by theory, it is believed that dithianes increase cellular non-protein SH, a primary objective in the treatment of presbyopia. Exemplary dithianes include, but are not limited to:
In one embodiment, the agent is a derivative of dithiothreitol (DTT) such as trans-4,5-dihydroxy-1,2-dithiane, also referred to herein as “non-lethal DTT”:
Both DTT and non-lethal DTT possess potent antioxidant properties, but non-lethal DTT possesses the further advantage of reduced toxicity thereby being more favorable for use in in vivo settings.
The active agent can be administered as a racemate or as an enantiomer. For example, lipoic acid and its derivatives are preferably administered to include the R form; cystine and its derivatives are preferably administered to include the L form. Synthetic methods to yield a racemate may be less expensive than stereo-specific processes including isolation/purification steps. On the other hand, administering a single enantiomer can lower the therapeutically effective amount, thus decreasing toxicity effects.
The agents described herein are preferably reducing agents. For example, the agents can possess a redox potential E0′(V) of about −0.01 to about −1.0, about −0.1 to about −0.5, about −0.2 to about −0.4, or about −0.3. The agents described herein preferably exhibit an acceptable toxicity profile, e.g., a median lethal dose (LD50) of at least 10 μM, at least 20 μM, at least 40 μM, or at least 1 mM. Toxicity can be assessed by any method known in the art such as, for example, viability of human umbilical vein endothelial cells (HUVEC, first passage) using the MultiTox-Fluor assay (Promega) or Live/Dead® assay (Invitrogen). Of course, agents selected as pharmaceutical agents for the treatment of presbyopia should exhibit both antioxidant efficacy (reducing power) as well as a desirable safety profile (low toxicity). Accordingly, in one embodiment, a screening method is provided whereby dithiol compounds or derivatives are tested for reducing power and/or toxicity. In another embodiment, a method includes screening dithiol compounds or dithiol derivatives for their ability to increase lens elasticity either in vitro or in vivo.
The agents described herein preferably exhibit favorable membrane permeability, specifically corneal permeability. Corneal penetration can be measured by methods known in the art, such as, for example, those disclosed in Kim et al. (2005) “Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients” Opthalmology 112(11): 1992-96. In one embodiment, the agent enters the lens epithelial cells using a naturally occurring transport mechanism. For example, lipoic acid and cystine enter lens cells via specific plasma membrane symporters and antiporters. By using lipoic acid, cystine, or derivatives thereof, one can utilize a naturally occurring transport mechanism to deliver the agents to the lens cells.
In another embodiment, a pharmaceutical composition includes an agent as described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may also contain one or more excipients as is well known in the art of pharmaceutical formulary. In one embodiment, the pharmaceutical composition is formulated for ocular use. That is, the pharmaceutically acceptable carrier and/or other excipients are selected to be compatible with, and suitable for, ocular use. Such carriers and excipients are well known in the art. The excipients may also be selected and/or formulated to improve the solubility of the compound. For example, the pharmaceutical composition can include one or more of emulsifiers, buffers, salts, preservatives, lubricants, polymers, solvents, and other known excipients for ocular pharmaceutical formulations. In one embodiment, the pharmaceutical composition includes an emulsifier and a buffered carrier such as Polysorbate 80 in HBSS (Hank's Balanced Salt Solution).
In another embodiment, the agents are employed in a method for treating ocular disease, e.g., presbyopia, by administering an effective amount of the agent. In another embodiment, the agents are employed in a method for preventing or reversing oxidative damage to cells, e.g., lens cells. The agents can be applied to lenses or cells in vitro or in vivo.
The term “effective amount” means an amount that is capable of preventing, reducing, reversing, and/or slowing the rate of oxidative damage. For ocular applications, a therapeutically effective amount may be determined by measuring clinical outcomes including, but not limited to, the elasticity, stiffness, viscosity, density, or opacity of a lens.
Lens elasticity decreases with age and is a primary diagnostic and causative factor for presbyopia. Lens elasticity can be measured as accommodative amplitude in diopters (D).
Lens elasticity can also be measured by the unit of elasticity E. The higher the value of E, the less elastic the lens.
Therapeutic efficacy can also be measured in terms of lens opacity. Lens opacity increases with age and is a primary diagnostic and causative factor for cataract.
Therapeutic efficacy can also be measured as a reduction in the rate of cell proliferation, particularly lens epithelial cell proliferation. Thus, in some embodiments, therapeutic efficacy can be measured by cytostatic effect.
Some agents described herein exist naturally in the untreated eye. Lipoic acid and cystine, for example, occur naturally in eye tissue. In general, a therapeutically effective amount of the exogenously administered agent is often at least about 1 or 2 orders of magnitude larger than the natural level of the agent. In one embodiment, the lipoic acid or derivative thereof is administered in a dose amount of up to about 1 mM. In one embodiment, the dose amount of lipoic acid or a derivative thereof is about 1 μM up to 1 mM, preferably about 0.25 mM to about 0.75 mM, or about 0.5 mM. In another embodiment, the dose amount of lipoic acid or derivative thereof is no more than 0.5 mM, 250 μM, 100 μM, 50 μM, 20 μM, or 10 μM. In another embodiment, cystine or a derivative thereof is administered in a dose amount of about 1 μM to about 20 μM. In yet another embodiment, the dose amount of cystine or a derivative thereof is no more than 20 μM, the limit of cystine solubility in aqueous solution, or no more than 15 μM, 12 μM, 10 μM, 7 μM, or 5 μM. The dose amount will depend on the route of administration as well as the age and condition of the patient. Similarly, the frequency of dosing will depend on similar factors as can be determined by one of ordinary skill in the art.
Efficacy has been demonstrated in vitro for specific exemplary dosing.
The methods include preventative methods that can be performed on patients of any age. The methods also include therapeutic methods that can be performed on patients of any age, particularly patients that are at least 20, 25, 30, 35, 40, 45, 50, 52, 55, 57, 60, 70, 75, or 80 years of age.
The agents described herein can be formulated to achieve any delivery system known in the art such as immediate or sustained release delivery; systemic, ocular, or localized delivery; topical or injection delivery; prodrug or caged delivery systems, e.g., coumarin cages (as described, for example, in co-pending application U.S. Ser. No. 12/267,260), etc.
The agents can be linked to, co-administered with, and/or co-formulated with other therapies such as other pharmaceutically active ingredients and/or energy sources (as described, for example, in co-pending application U.S. Ser. No. 11/946,659). In one embodiment, the agent is co-administered with chemical energy, such as, for example glucose-6-phosphate (G6P), NADPH, or glucose. In one embodiment, the agent is activated by an endogenous chemical energy, e.g., endogenous glucose. For example, endogenous glucose can activate lipoic acid or a derivative thereof to dihydrolipoic acid (DHLA) or a corresponding derivative thereof.
The agents can be formulated as a pharmaceutically acceptable salt.
The agents can be administered to a lens by any route of administration including, but not limited to, topical, subtenons, subconjunctival, intracameral, intravitreal, or iontophoresis routes. In one embodiment, the agent can be delivered topically, e.g., via an eye drop, gel, ointment, or salve. In other embodiment, the compound can be delivered via an acute delivery system, e.g., using nanotubes, local injection, micro-injection, syringe or scleral deposition, or ultrasound.
The disclosures of all references and publications cited above are expressly incorporated by reference in their entireties.
Any numerical values recited herein include all values from the lower value to the upper value in increments of any measurable degree of precision. For example, if the value of a variable such as age, amount, time, percent increase/decrease and the like is 1 to 90, specifically from 20 to 80, and more specifically from 30 to 70, it is intended that values such as 15 to 85, 22 to 68, 43 to 51, 30.3 to 32, etc., are expressly enumerated in this specification. In other words, all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.
Although particular features have been described with respect to particular embodiment as illustrative, one of ordinary skill in the art would recognize that any particular feature could be applied to any of the embodiments described herein. Various modifications and variations of the described agents, compositions, and methods will be apparent to those skilled in the art without departing from the scope and spirit of the invention. To further illustrate particular embodiments of the invention, we provide the following non-limiting examples.
Increase in Elasticity: Pairs of mouse lenses were incubated in medium 200 supplemented with an antibiotic, an antimycotic, in the presence or absence of lipoic acid (concentrations ranging from 0.5 μM to 500 μM) for 8-15 hours. Each lens was removed from medium, weighed, and photographed on a micrometer scale. A coverslip of known weight (0.17899±0.00200 g) was placed on the lens, and the lens was photographed again on the micrometer scale. The diameter of each lens with and without the coverslip was determined from the photographs. The change in lens diameter produced by the force (coverslip) was computed ΔD=(Dwithcoverslip−Dwithoutcoverslip). The results (
Decrease in disulfide bonds: Lipoic acid at concentrations≧9.6 μM caused a statistically significant decrease in protein disulfides in the mouse lenses where there was a significant increase in ΔD (
This application claims the benefit of U.S. Provisional Patent Application 61/033,870 filed Mar. 5, 2008, U.S. Provisional Patent Application 61/060,487 filed Jun. 11, 2008, and U.S. Provisional Patent Application 61/077,186 filed Jul. 1, 2008. Each of these is incorporated herein by reference in its entirety.
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| Number | Date | Country | |
|---|---|---|---|
| 20090192212 A1 | Jul 2009 | US |
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| 61033870 | Mar 2008 | US | |
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| 60861262 | Nov 2006 | US | |
| 60907734 | Apr 2007 | US | |
| 60924686 | May 2007 | US | |
| 60574211 | May 2004 | US | |
| 60262423 | Jan 2001 | US | |
| 60225659 | Aug 2000 | US |
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