WO2015187850A2 - Composés et méthodes destinés au traitement de troubles oculaires - Google Patents

Composés et méthodes destinés au traitement de troubles oculaires Download PDF

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WO2015187850A2
WO2015187850A2 PCT/US2015/034016 US2015034016W WO2015187850A2 WO 2015187850 A2 WO2015187850 A2 WO 2015187850A2 US 2015034016 W US2015034016 W US 2015034016W WO 2015187850 A2 WO2015187850 A2 WO 2015187850A2
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alkyl
compound
aryl
halo
hydroxyl
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PCT/US2015/034016
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WO2015187850A3 (fr
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Scott Cousins
David M. Gooden
Priyatham METTU
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Duke University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone

Definitions

  • the present disclosure relates generally to the treatment of disorders of the eye, and more specifically relates to compounds, methods, formulations, and drug delivery systems for the treatment of ocular diseases including posterior segment eye disorders, such as age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the disclosure finds utility in the fields of ophthalmology, pharmacology, and pharmaceutical formulation.
  • AMD is the most common aging-related ophthalmic disorder today, and causes irreversible loss of vision. AMD is a progressive condition that is untreatable in up to 90% of patients, and is a leading cause of blindness in the elderly.
  • the medical and societal burden caused by this pervasive and serious disorder is extremely high: as of 2003, the United Nations estimated the number of people with age-related macular degeneration at 20 to 25 million worldwide, and that number is expected to triple in the next twenty or thirty years. Furthermore, according to the United National National's recent predictions, the population of individuals over eighty is expected to increase from 69 million in 2000 to 379 million by the year 2050, exacerbating an already dire problem.
  • the present disclosure addresses the aforementioned need in the art by providing a composition, method, formulation, and drug delivery system for treating an ocular disease such as a posterior segment eye disorder in a patient.
  • an ocular disease such as a posterior segment eye disorder
  • the ocular disease can be dry or wet age-related macular degeneration.
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from hydrogen; halo; hydroxyl; cyano; nitro; amine; carboxyl; Ci-i 2 (e.g., C1-3) alkoxyl optionally substituted with 1 or more Ci-i 2 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g., C2-3) alkynyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, C4-12 heteroaryl, carboxyl, amine, oxo, hydroxyl, cyano and/or halo; Ci-12 (e.g., C1-3) carbonyl optionally substituted with 1 or more Ci i2 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g.,
  • each of R 6 , R 7 , R 8 and R 10 is independently selected from hydrogen and Ci-6 (e.g., C1-3) alkyl, C2-6 (e.g., C2-3) alkenyl or C2-6 (e.g., C2-3) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, carboxyl, oxo, cyano, nitro, and/or amine;
  • R 9 is selected from -0-R-, -N(H)-R-, -N(R)R-, -S-R-, -S(0)-R-, -S(02 R-, -C(0)-R-, -C(0)0-R- and -R-, wherein each R is independently selected from Ci-12 alkyl, C2-12 alkenyl and C2-12 alkynyl, each optionally substituted with 1 or more halo, hydroxyl, carboxyl, oxo, cyano, nitro, and/or amine;
  • A is selected from Ci-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-i2 aryl, and C4-12 heteroaryl;
  • X is selected from C, O, and N.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, hydroxyl, Ci-6 alkyl, and Ci-6 carboxyl, wherein at least one of R 1 , R 2 , R 3 , and R 4 is Ci-6 carboxyl;
  • R 5 is selected from hydrogen, hydroxyl, Ci- 6 alkoxyl, amine, nitro, cyano, halo, and Ci-6 alkyl optionally substituted with one or more halo;
  • each of R 6 , R 7 , R 8 and R 10 is independently selected from hydrogen and Ci-6 alkyl;
  • R 9 is-O-R-
  • A is selected from Ci-12 alkyl and C6-12 aryl
  • X is selected from CH, O, and N.
  • Alk represents a Ci-12 alkyl group optionally substituted with one or more halo, hydroxyl, carboxyl, oxo, cyano, nitro, amine, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, and C4-12 heteroaryl;
  • Z is selected from H, CH3 and CF3; and
  • Y is CH or N.
  • the compound or salt of formula (I) or (II) can be selected from the group consisting of:
  • a pharmaceutical composition which includes the compound or salt described herein.
  • the pharmaceutical composition can further include a pharmaceutically acceptable carrier.
  • the formulation can include an injectable composition, i.e., a composition for periocular or intravitreal administration.
  • a method for treating an ocular disease includes administering an effective amount of the compound or salt described herein as an active agent to a patient in need thereof.
  • the active agent is generally administered in a pharmaceutical formulation that comprises a pharmaceutically accepted vehicle, where the formulation is adapted to a particular mode of administration.
  • the active agent may be orally administered or systemically administered in some other manner, or the agent may be administered to the eye via topical administration, periocular or intravitreal injection, or by way of an implanted ophthalmic drug delivery system.
  • a method for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, in combination with administration of a therapeutically effective amount of an additional active agent.
  • the additional active agent may also be a therapeutic agent indicated for the same posterior segment eye disorder, or it may potentiate the activity of the initial agent, or it may be indicated for another related or unrelated eye disorder.
  • a method for treating an ocular disease by administering an effective amount of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein, upon administering, the compound or salt binds to at least one retinoid X receptor (RXR) for treating the ocular disease.
  • RXR retinoid X receptor
  • the compound or salt can activate the at least one RXR.
  • the compound or salt can increase one or both of heterodimerization and homodimerization of the at least one RXR.
  • the compound or salt can form at least one heterodimer with at least one RXR and at least one nuclear receptor protein.
  • the at least one RXR can be one or more of RXRa, RXR , or RXRy.
  • a method for treating or preventing an ocular disease such as a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, where the active agent is administered periodically, at regular intervals or as needed, throughout an ongoing dosage regimen, e.g., daily, weekly, monthly, etc., for an extended time period, e.g., two months, four months, six months, one year, two years, or longer.
  • a method for treating or preventing an ocular disease such as a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, where the active agent is administered in a controlled release formulation such that drug release occurs gradually and over a sustained time period, as may be accomplished with a controlled release injected formulation, a controlled release implant, or the like.
  • a drug delivery system for treating a patient with an ocular disease such as a posterior segment eye disorder, where the system provides for controlled release of an active agent as described herein into the eye of a patient in need thereof, and the system includes a biodegradable polymeric implant, a nonbiodegradable polymeric implant, a nonpolymeric implant, an iontophoretic delivery device, an ultrasound- activated drug delivery system, a drug-releasing contact lens, a drug-coated microneedle system, a microelectromechanical system (MEMS) delivery device, or a refillable port system.
  • an ocular disease such as a posterior segment eye disorder
  • the system includes a biodegradable polymeric implant, a nonbiodegradable polymeric implant, a nonpolymeric implant, an iontophoretic delivery device, an ultrasound- activated drug delivery system, a drug-releasing contact lens, a drug-coated microneedle system, a microelectromechanical system (MEMS) delivery device, or a
  • Fig. 1 shows the domains of bexarotene and literature compounds.
  • Fig. 2 shows a schematic for the synthesis for the synthesis of Formula I and II.
  • FIG. 3 shows treatment of cultured RPE cells (ARPE-19) with RXR agonist compounds and the effect of these compounds on the expression levels of ABCG1.
  • Data is presented for treatment with BEX (bexarotene), a known RXR agonist, and Compound 9, which represents a new chemical entity described in paragraph [0019].
  • FIG. 4 shows treatment of cultured RPE cells (ARPE-19) with RXR agonist compounds and the effect of these compounds on the expression levels of ABCA1.
  • Data is presented for treatment with BEX (bexarotene), a known RXR agonist, and Compound 9, which represents a new chemical entity described in paragraph [0019].
  • BEX bexarotene
  • an active agent includes a single active agent as well as a combination or mixture of two or more different active agents
  • a vehicle or excipient includes not only a single vehicle or excipient but also a combination or mixture of two or more different vehicles and excipients, and the like.
  • the terms “about” and/or “approximately” may be used in conjunction with numerical values and/or ranges.
  • the term “about” is understood to mean those values near to a recited value.
  • “about 40 [units]” may mean within + 25% of 40 ⁇ e.g. , from 30 to 50), within + 20%, + 15%, + 10%, + 9%, + 8%, + 7%, + 6%, + 5%, + 4%, + 3%, + 2%, + 1%, less than + 1 %, or any other value or range of values therein or therebelow.
  • the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein.
  • the terms “about” and “approximately” may be used interchangeably.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • controlled release includes sustained release, modified release and delayed release formulations.
  • controlled release includes “sustained release” (synonymous with “extended release”), referring to a formulation that provides for gradual release of an active agent over an extended period of time, as well as “delayed release,” indicating a formulation that, following administration to a patient, provides for a measurable time delay before the active agent is released from the formulation into the body of the patient, e.g., the eye.
  • drug form denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration.
  • the frequency of administration that will provide the most effective results in an efficient manner without overdosing will vary with the characteristics of the particular active agent, including both its pharmacological characteristics and its physical characteristics.
  • an agent that is nontoxic and effective for producing a therapeutic effect upon administration to a subject.
  • ocular disease means and includes any disorder, disease, or perturbed function of the eye and surrounding ocular adnexae (including conjunctiva, connective tissue, extraocular muscles, periorbital tissues, and eyelids).
  • Ocular disorders include posterior segment eye disorder(s) such as dry age-related macular degeneration, neovascular age-related macular degeneration, other causes of choroidal neovascularization (including ocular histoplasmosis, traumatic, myopia and others), diabetic retinopathy with or without diabetic macular edema, other causes of macular edema, other causes of retinal neovascularization, retinal detachments from any cause (including tractional, exudative or rhegmatogenous), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, other vascular retinopathies (including hypertensive and macular telangiectasia), retinitis pigmentosa and other retinal degenerations, panuveitis, glaucoma, posterior uveitis, AIDS-related retinitis and endophthalmitis, as well as anterior segment disorders,
  • the term "patient” or “individual” or “subject” refers to any person or mammalian subject for whom or which therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the disclosure.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable when used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • pharmaceutically acceptable salts include acid addition salts of basic agents which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, mandelic acids, and the like.
  • compositions of acidic agents can be prepared with inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, or with organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides
  • organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.
  • “Pharmacologically active” refers to a compound having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • any numerical range recited herein includes all values from the lower value to the upper value.
  • concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1 % to 3%, etc., are expressly enumerated in this specification. It is to be understood that these ranges comprise all subranges therein.
  • range "from 50 to 80" includes all possible ranges therein (e.g. , 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.).
  • acyl refers to substituents having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl
  • acyloxy refers to substituents having the formula -O(CO)- alkyl, -0(CO)-aryl, or -0(CO)-aralkyl, wherein "alkyl,” “aryl, and “aralkyl” are as defined above.
  • alicyclic is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or poly cyclic.
  • alkaryl refers to an aryl group with an alkyl substituent
  • aralkyl refers to an alkyl group with an aryl substituent, wherein “aryl” and “alkyl” are as defined above.
  • Preferred aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms.
  • aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4- benzylcyclohexylmethyl, and the like.
  • Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctyinaphthyl, 3- ethyl-cyclopenta- 1 ,4-diene, and the like.
  • alkaryloxy and aralkyloxy refer to substituents of the formula -OR wherein R is alkaryl or aralkyl, respectively, as just defined.
  • alkenyl refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • alkenyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms.
  • the term "lower alkenyl” intends an alkenyl group of 2 to 4 carbon atoms.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like.
  • alkyl groups herein contain 1 to about 18 carbon atoms, preferably 1 to about 12 carbon atoms.
  • lower alkyl intends an alkyl group of 1 to 6 carbon atoms. Preferred lower alkyl substituents contain 1 to 4 carbon atoms.
  • Substituted alkyl refers to alkyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively.
  • aryloxy refers to an aryl group bound through a single, terminal ether linkage, wherein "aryl” is as defined above.
  • An "aryloxy” group may be represented as -O-aryl where aryl is as defined above.
  • Preferred aryloxy groups contain 5 to 24 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms.
  • aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, m-halo- phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxyphenoxy, 3,4,5-trimethoxy-phenoxy, and the like.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 4 carbon atoms.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy” group may be represented as -O-alkyl where alkyl is as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc.
  • Preferred lower alkoxy substituents contain 1 to 3 carbon atoms, and particularly preferred such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).
  • alkenyloxy and “alkynyloxy” are defined in an analogous manner.
  • amine includes primary (— NH 2 ), secondary (— NHR), tertiary (— NRR'), and quaternary (— N + RR'R”) amine having one, two or three independently selected substituents R, R' , and R' ' such as straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, and the like.
  • R, R' , and R' ' such as straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, and the like.
  • R' , and R' ' such as straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, and the like.
  • azide refers to a group of formula— N 3 .
  • nitro refers to
  • aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms.
  • Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
  • Substituted aryl refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom containing aryl and “heteroaryl” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term “aryl” includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents.
  • cyano employed alone or in combination with other terms, refers to a group of formula— CN, wherein the carbon and nitrogen atoms are bound together by a triple bond.
  • cyclic refers to alicyclic or aromatic substituents that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or poly cyclic.
  • halo and halogen are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.
  • heteroatom-containing refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur, preferably nitrogen or oxygen.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1 ,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc.
  • Hydrocarbonyl refers to univalent hydrocarbonyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 18 carbon atoms, most preferably about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like.
  • Substituted hydrocarbonyl refers to hydrocarbonyl substituted with one or more substituent groups
  • heteroatom-containing hydrocarbonyl refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term “hydrocarbonyl” is to be interpreted as including substituted and/or heteroatom-containing hydrocarbonyl moieties.
  • substituted as in “substituted alkyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation: functional groups such as halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2- C24 alkynyloxy, C5-C24 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C24 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C24 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X where X is halo), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C24 arylcarbonato (-O-(CO)-O-aryl), carboxy (- COOH), carboxylato (-COO-),
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbonyl moieties such as those specifically enumerated above.
  • the abovementioned hydrocarbonyl moieties may be further substituted with one or more functional groups or additional hydrocarbonyl moieties such as those specifically enumerated.
  • substituted appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.
  • substituted alkyl, alkenyl, and aryl is to be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.
  • heteroatom-containing appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group.
  • heteroatom-containing alkyl, alkenyl, and aryl is to be interpreted as “heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.”
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2NH- optionally also recites -NHCH2-.
  • [0071] is used in structural formulae herein to depict a bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the active agent is an agonist of the retinoid X receptor (RXR), i.e., the agent is a compound or composition that stimulates the biological activity of the retinoid-associated nuclear receptor RXR.
  • RXR retinoid X receptor
  • retinoids are produced naturally across all living species. Endogenous retinoids such as carotenoids are essential for myriad biological processes including regulation of cellular proliferation, ensuring proper function of vision, and activation of immune response. In addition to the activity of naturally occurring retinoids, synthetically derived retinoids can also modulate specific biological processes and thus have utility in clinical medicine. For example first generation synthetic retinoids such as retinol and isotretinoin, have been used mostly in the treating diseases of the skin. Later generations of synthetic retinoids, most notably the antineoplastic agent bexarotene, have been used to treat refractory cutaneous T-cell lymphoma. Additionally, bexarotene is being investigated for use in the treatment of breast cancer, lung cancer, noninsulin-dependent diabetes mellitus, and Alzheimer' s disease.
  • endogenous retinoids such as carotenoids are essential for myriad biological processes including regulation of cellular proliferation, ensuring proper function of vision, and activation of immune response.
  • RXR-NRP heterodimers are in fact responsible for activation of various transcriptional factors which regulate processes such as lipid and glucose metabolism and immune response. These heterodimers are known to be activated by RXR agonists thus the development of novel, selective and potent RXR agonists represent a valid and continuing endeavor in drug development. Indeed a great deal of research has been devoted to the development of RXR agonists.
  • RXR agonists increase the ability of the RXR to activate transcription of genes including those that control cellular differentiation and proliferation.
  • RXR agonist encompasses prodrugs and precursors as well as RXR agonists per se, i.e., compounds that are therapeutically inactive as administered but that are converted to an active RXR agonists in the body, following administration.
  • the agent may or may not in addition be a modulator of the retinoic acid receptor (RAR), although in an embodiment the agent is not an RAR agonist but rather is RXR-selective.
  • RAR retinoic acid receptor
  • RXR selective or non-selective agonists of the RXR, including partial agonists, are generally preferred for use in conjunction with the methods and formulations of the present disclosure. It should be noted that when the term "agonist" is used herein, it is intended to include partial agonists. In the presence of an RXR agonist, it is generally accepted that the receptor undergoes a conformational change that results in an increase in the transcriptional regulation activity of RXR, RXR homodimers, and/or RXR heterodimers.
  • RXR is known to form a dimer either with itself, in which case the dimer is an "RXR homodimer," or with another receptor such as a nuclear receptor protein, e.g., the thyroid receptor, the vitamin D receptor, or the peroxisome proliferator- activated receptor, in which case the dimer is an "RXR heterodimer.
  • RXR agonist as provided herein can, in some embodiments, increase the transcriptional regulation activity of any of the foregoing.
  • a well-known RXR agonist is bexarotene.
  • the general structure of bexarotene and bexarotene-based RXR agonists consists of three distinct domains: 1) a lipophilic domain characterized by a 1,1 ,4,4-tetramethyltetralin moiety, 2) a linking domain and 3) an acidic domain.
  • Representative examples of bexarotene-based compounds are shown in Figure 1. Even though bexarotene has received FDA approval, side effects including hypothyroidism, hyperlipidemia, weight gain and cutaneous toxicity at the therapeutic concentration leave the door open for the development of new analogs which act as potent and selective RXR agonists while attenuating undesirable side effects.
  • Alk represents a Ci-12 alkyl group optionally substituted with one or more halo, hydroxyl, carboxyl, oxo, cyano, nitro, amine, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, and C4-i2 heteroaryl;
  • Z is selected from H, CH3 and CF3; and
  • Y is CH or N.
  • the compound can be one or more of:
  • an active agent whether specified as a particular compound or a compound class (e.g., an RXR agonist)
  • the term used to refer to the agent is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs and derivatives, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, hydrates, crystalline forms, enantiomers, stereoisomers, and other such compounds.
  • an intermediate compound 7 can be synthesized according to Scheme 1 : Witting olefination on 4' -bromo-2' -hydroxyacetophenone followed by hydrogenation using a palladium catalyst produces 5-bromo-2-isopropylphenol, from which compound 16 can be synthesized using a commercially available alkyl halide or other halides. Depending on the specific halide, a large number of compounds can be synthesized. In certain embodiments, the halide can be selected such that the resulting -O-Alk group on compound 16 is lipophilic.
  • methods to quantify RXR agonist activity are publicly available, e.g., as detailed by Johnson et al. (1999) "Retinoid X Receptor (RXR) Agonist- Induced Activation of Dominant-Negative RXR-Retinoic Acid Receptor alpha403 Heterodimers is Developmentally Regulated during Myeloid Differentiation," in Molecular and Cellular Biology 19:5, 3372-3382, and is hereby incorporated by reference.
  • the methods in Johnson et al. are used to characterize an increase in RXR dimer formation.
  • Compounds described herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomer, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a compound described herein may be an enantiomerically enriched isomer of a stereoisomer described herein.
  • the compound may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid.
  • the compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • the enantiomers also may be obtained from kinetic resolution of the racemate of corresponding esters using lipase enzymes.
  • H may be in any isotopic form, including 3 ⁇ 4 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • a compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt.
  • Neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure. Examples of pharmaceutically acceptable salts are discussed in Berge et al., (1977) "Pharmaceutically Acceptable Salts.” /. Pharm. Sci. Vol. 66, pp. 1-19.
  • a salt form may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as ammonium ion (i.e., NH4 "1" ).
  • Suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NH3R1 "1” , NH2R2 “1” , NHR3 "1” , NR 4 + ).
  • substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • a salt form may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2- acetyoxy benzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, gluchep tonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Functional groups present in the molecular structure of active agents useful herein may or may not be protected, and it is intended that both protected and unprotected forms be encompassed herein.
  • a functional group is "protected” if the group is in modified form to preclude undesired reactions at the protected site.
  • Suitable protecting groups for compounds herein will be apparent to those of ordinary skill in the art ad/or described in the pertinent texts and literature; see, e.g., the level of skill in the art, and with reference to standard textbooks, such as Greene et al., Protective Groups in Organic Synthesis (New York: Wiley, 1999), incorporated by reference herein.
  • the present disclosure may also provide compounds that are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds described herein.
  • Prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • a compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom substitution in aromatic rings.
  • the method of the disclosure involves treatment or prevention of an ophthalmic disorder in a patient by administering to the patient a therapeutically effective amount of an active agent as described herein.
  • the active agent may be administered to the patient by itself or more typically in a formulation, dosage form (e.g., a unit dosage form), or drug delivery system, such as an implant or the like.
  • patients who benefit from the present method are those who are prone to or afflicted with an ophthalmic disorder, generally although not necessarily involving the posterior segment of the eye.
  • An active agent as described herein may be administered in the context of monotherapy, or it may be combined with another active agent as described herein (i.e., in the same structural family or functional class) and/or with a different class of active agent. With combination therapy, the active agents may be administered separately, in separate formulations or dosage forms, or simultaneously, either in one dosage form or in two or more different dosage forms.
  • compositions, dosage forms, and drug delivery systems suitable for use in conjunction with the present disclosure contain a "therapeutically effective" amount of the active agent or agents, i.e., an amount effective to achieve the intended purpose. Determination of a therapeutically effective amount for a particular active agent is well within the capability of those skilled in the art of ophthalmology and ocular pharmacotherapy.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as improved pathology of age-related macular degeneration or another disorder of the eye.
  • a therapeutically effective amount of a compound may vary according to factors such as the mode of administration, disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. Doses for oral administration can range from about 0.1 mg/kg/day to about 100 mg/kg/day while doses suitable for topical or injectable administration are typically in the range of about 0.01 mg/ml to about 100 mg/ml. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • Administration of an active agent to treat or prevent an ophthalmic disorder may be carried out using any appropriate mode of administration.
  • administration can be, for example, systemic (e.g., oral), or it may be topical, periocular, or intravitreal.
  • systemic administration via the oral route may be preferred for some drugs, although the frequency of dosing necessary to maintain therapeutic blood levels of drug in the target tissue of the eye can result in non-specific absorption and undesirable systemic side effects.
  • oral drug administration will typically be limited to active agents that have limited systemic side effects and high therapeutic indices, and that are well tolerated when administered via the oral route.
  • topical drug delivery is generally viewed as the preferred route of administration for many drugs, as systemic, e.g., oral, delivery may be problematic for the reasons outlined above.
  • Topical formulations are convenient for the patient to use, thus minimizing problems with patient compliance.
  • preparation of topical ophthalmic formulations such as eye drops, ointments, and the like is normally straightforward and does not, typically, involve complex or costly manufacturing techniques.
  • topical drug delivery to the eye is carried out by administration of a formulation containing a pharmaceutically acceptable vehicle and one or more excipients.
  • the formulation may be aqueous, partially aqueous, or nonaqueous, and the ophthalmic vehicle selected will depend on the particular type of formulation.
  • a topically administrable composition can be formulated as aqueous solution for a water- soluble drug, or as an ophthalmic suspension for a drug with lower aqueous solubility.
  • the vehicle is aqueous, and in the latter case, the vehicle will be only partially aqueous.
  • Formulations for topical administration to the eye may also be in the form of an ointment, in which case the pharmaceutically acceptable carrier is composed of an ointment base.
  • Preferred ointment bases have a melting or softening point close to body temperature, and any ointment bases commonly used in ophthalmic preparations may be advantageously employed.
  • Common ointment bases include petrolatum and mixtures of petrolatum and mineral oil.
  • Topical formulations are normally preferred for treating and preventing disorders of the anterior segment of the eye, e.g., disorders of the cornea, conjunctiva, and sclera, but are not typically preferred for treating and preventing disorders of the posterior segment of the eye, e.g., disorders of the retina, choroid, vitreous humor, and optic nerve.
  • disorders of the anterior segment of the eye e.g., disorders of the cornea, conjunctiva, and sclera
  • disorders of the posterior segment of the eye e.g., disorders of the retina, choroid, vitreous humor, and optic nerve.
  • the leading causes of vision impairment and blindness are posterior segment-linked disorders, and it is thus imperative to ensure that an active agent can reach the target tissue at therapeutic levels.
  • Posterior segment-linked disorders include, without limitation, age-related macular degeneration, macular edema (including diabetic macular edema), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, retinitis pigmentosa, retinal detachment, diabetic retinopathy, retinal degeneration, vascular retinopathy, uveitis, AIDS-related retinitis, choroidal and retinal neovascularization, and macular telangiectasia.
  • the formulation and/or mode of administration be modified so as to increase the retention time of the drug in the eye.
  • an ophthalmic permeation enhancer may be incorporated into the formulation, or a punctal plug can be used in conjunction with topical administration, or the like.
  • Punctal plugs are devices that are inserted into the tear duct (or "puncta") of the eye to prevent drainage of liquid. Punctal plugs may be gradually soluble in aqueous fluid and thus temporary (as is the case with collagen plugs, for instance) or they may be inert and thus permanent (a silicone plug such as that available from FCI Ophthalmics as Snug PlugsTM is one example).
  • the selected active agent is administered to treat or prevent an ocular disorder using either the periocular or intravitreal routes, with the formulation, dosage form, or delivery system adapted to the selected mode of administration.
  • periocular and intravitreal administration overcome the occasional disadvantages that can be associated with systemic or topical drug administration, as alluded to earlier herein.
  • Periocular administration encompasses four distinct types of injection into the eye, i.e., subconjunctival, sub-tenon, retrobulbar, and peribulbar.
  • Active agents administered by periocular injection can reach the targeted tissue in the posterior segment of the eye by at least one of three pathways: transcleral; systemic circulation through the choroid; and the anterior pathway through the tear film, cornea, aqueous humor, and the vitreous humor.
  • transcleral adenosarcoma
  • systemic circulation through the choroid
  • anterior pathway through the tear film, cornea, aqueous humor, and the vitreous humor.
  • subconjunctival injection is generally preferred insofar as the potentially rate limiting conjunctival epithelial barrier is avoided.
  • intravitreal injections bypass the choroid and blood-retinal barriers by direct administration into the vitreous.
  • Controlled release formulations - preferably sustained formulations— for topical, periocular, and intravitreal administration are generally preferred to ensure that the active agent is continuously reaching the target tissue of the eye. These systems additionally reduce the frequency of drug administration, assist in overcoming blood-ocular tissue barriers, and can enhance the stability of a formulation.
  • a variety of controlled release compositions, dosage forms, and drug delivery systems such as ocular implants have been developed. See, e.g., Kuno and Fujii (May/June 2012) Retina Today, pp. 54-59; Gaudana et al. (2010) AAPS Journal 12(3):348-360; Haders (July/August 2008) Drug Delivery Technology 8(7):48-53; Kompella et al.
  • injectable formulations including formulations designed for either periocular or intravitreal injection, can be manufactured so as to contain surface-modified nanospheres to enhance diffusion, e.g., nanospheres having covalently or otherwise attached surface hydrophilic groups (such as low molecular weight polyethylene glycol), or nanospheres treated so as to have surface anionic groups.
  • surface-modified nanospheres e.g., nanospheres having covalently or otherwise attached surface hydrophilic groups (such as low molecular weight polyethylene glycol), or nanospheres treated so as to have surface anionic groups.
  • compositions containing drug-loaded liposomes, microparticles, and nanoparticles Colloidal formulations that provide for controlled release of active agent have also been prepared, including compositions containing drug-loaded liposomes, microparticles, and nanoparticles.
  • the surfaces of the agent containing particles may be electrically neutral, or they may be ionized; cationic surfaces are usually preferred to enhance the passage through the negatively charged corneal epithelial mucosa. Cationic liposomes are one possibility.
  • Chitosan-coated nanoparticles are also in use, insofar as the amino groups of chitosan have a pKa of about 6.5, in turn meaning that the surface amino groups are protonated at physiological pH.
  • the active agent may also be formulated in a lipid-based composition, typically a w/o or o/w surfactant- containing emulsion.
  • Excipients for topically administrable and injectable ophthalmic formulations typically include, by way of illustration, thickeners, isotonic agents, buffering agents, preservatives, release rate-controlling excipients, and solubility modulators.
  • thickeners examples include cellulosic polymers such as methylcellulose (MC), hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC); other swellable hydrophilic polymers such as polyvinyl alcohol (PVA), hyaluronic acid or a salt thereof (e.g., sodium hyaluronate); and crosslinked acrylic acid polymers commonly referred to as "carbomers” (and available from B.F. Goodrich as Carbopol® polymers).
  • PVA polyvinyl alcohol
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropyl-methylcellulose
  • NaCMC sodium carboxymethylcellulose
  • other swellable hydrophilic polymers such as polyvinyl alcohol (PVA), hyaluronic acid or a salt thereof (e.g., sodium hyaluronate); and crosslinked acrylic acid polymers commonly referred to as
  • any thickener is such that a viscosity in the range of about 15 cps to 25 cps is provided, as a formulation having a viscosity in the aforementioned range is generally considered optimal for both comfort and retention of the formulation in the eye.
  • Any suitable isotonic agents and buffering agents commonly used in ophthalmic formulations may be used, providing that the osmotic pressure of the solution does not deviate from that of lachrymal fluid by more than 2-3% and that the pH of the formulation is maintained in the range of about 6.5 to about 8.0, preferably in the range of about 6.8 to about 7.8, and optimally at a pH of about 7.4.
  • Preferred buffering agents include carbonates such as sodium and potassium bicarbonate.
  • Solubility modulators for facilitating the incorporation of water-insoluble drugs into ophthalmic formulations include complexing agents such as cyclodextrins, surfactants (e.g., polyoxyethylated nonionic surfactants; see Jiao (2008) Advanced Drug Delivery Reviews 60: 1663-1673), and gums such as gum arabic, guar gum, hydroxypropyl guar gum, xanthan gum, locust bean gum, and agar gum.
  • Ocular implants that provide for controlled release of active agent in the eye include both nonbiodegradable drug delivery systems as well as drug delivery systems that will gradually hydrolyze, dissolve, or otherwise degrade in the eye.
  • suitable sites for these ocular delivery systems will be the same as those sites that are appropriate to receive the active agent by periocular or intravitreal injection, although implants may also be placed in the conjunctival cul-de-sac, or inferior fornix.
  • Nonbiodegradable implants are typically formulated from an inert, biocompatible, nonhydrolyzable polymer that provides for long- term sustained release of active agent, on the order of at least one month, three months, six months, one year, or even two years.
  • One such implant is that available from Surmodics Inc.
  • Biodegradable drug delivery systems may be made from gradually hydrolyzing, dissolving, or otherwise biodegrading polymers such as those in the poly-a- hydroxy acid family, e.g., polylactic acid, polyglycolic acid, and poly(lactide-co-glycolide), a copolymer thereof.
  • Still other controlled release delivery systems include refillable micropumps (in a MEMS -based drug delivery devices such as that under development by Replenish Inc.) and refillable port drug delivery systems (such as that under development by Genentech and ForSight Vision 4 Inc.), drug-coated microneedles (see Jiang et al. (2007) Invest. Ophthalmol. Vis. Sci. 48(9):4038043, and systems for co-delivering the active agent with microparticles of an enzyme that hydrolyzes the collagenous and extracellular matrix of the sclera (Jiang et al. (2009) Pharm. Res. 26(2): 395 -403.
  • Additional delivery systems useful in conjunction with the present method include ultrasound- mediated drug delivery (see Zderic et al. (2004) Cornea 23(8):804-l l); ocular iontophoresis (see Guadana et al. (2010) AAPS 12(3):348-360; and drug-releasing, drug-loaded contact lenses such as the PLGA/poly(2-hydroxyethyl methacrylate) lenses described by Nash, "Drug-Dispensing Contact Lens could Replace Imprecise Eye Drops,” in Scientific American (March 12, 2009).
  • ultrasound- mediated drug delivery see Zderic et al. (2004) Cornea 23(8):804-l l
  • ocular iontophoresis see Guadana et al. (2010) AAPS 12(3):348-360
  • drug-releasing, drug-loaded contact lenses such as the PLGA/poly(2-hydroxyethyl methacrylate) lenses described by Nash, "Drug-Dispensing Contact Lens could Replace Imprecise Eye Drop
  • the disclosure is generally directed to methods for treating or preventing an ocular disorder, such as AMD.
  • the retina is a complex multilayered structure, but may be viewed as composed of two functional parts: first, the photosensitive layer of rods and cones and neural connections that gather light and convert it to nerve impulses transmitted via the optic nerve; second, the underlying retinal pigment epithelium and its basal layer called Bruch's membrane, which together maintain the structural integrity of the barrier between the retina and the choroid, the main source of blood supply to the outer half of the retina.
  • the macula is the central area of the retina, composed primarily of cone cells and typically in the range of about 1 mm to 5 mm in diameter.
  • the fovea is at the center of the macula, contains the largest concentration of cone cells in the eye, and is the thinnest region of the retina. It is the fovea that is responsible for central, high resolution vision. In a healthy eye, this area is free of blood vessels and is referred to as the capillary-free zone.
  • Macular degeneration refers to the progressive destruction of the macula, and while some macular degeneration occurs in younger individuals, the term generally refers to age-related macular degeneration (AMD or ARMD).
  • AMD age-related macular degeneration
  • the two forms of AMD are "wet” AMD (also referred to as neovascular AMD) and “dry” AMD (also referred to as atrophic or nonneovascular AMD), depending on the respective presence or absence of new blood vessels that have invaded the retina.
  • AMD begins with the appearance of drusen in the macula, i.e., macromolecular deposits between the retinal pigment epithelium and the choroid. While some people with drusen can still have good vision, it is fairly common for people with drusen to develop advanced AMD, as large and numerous drusen can disturb the pigmented cell layer under the macula. Visual acuity can drastically decrease, or there can be a gradual loss of central vision, with blurring in the region of focus. It can become difficult to discern colors or even distinguish dark from light, and recovery of visual function after exposure to bright light becomes slow. Currently, no medical or surgical treatment is available for this condition.
  • Dry AMD can often lead to wet AMD, in which abnormal blood vessel growth in the macula leads to bleeding, leaking, and scarring, causing irreversible damage to the photoreceptors and rapid loss of vision.
  • Effective therapies for AMD may also be useful in the treatment or prevention of other ocular disorders.
  • the disclosure may therefore also provide methods of treating or preventing other disorders of the retina as well as disorders of the choroid, vitreous humor, and optic nerve.
  • disorders include, for example, macular edema (including diabetic macular edema), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, retinitis pigmentosa, retinal detachment, diabetic retinopathy, retinal degeneration, vascular retinopathy, uveitis, AIDS-related retinitis, choroidal and retinal neovascularization, and macular telangiectasia.
  • COS-1 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% FBS in a humidified atmosphere of 5% C02 at 37 °C.
  • Luciferase reporter gene assays were performed using COS-1 cells transfected with three kinds of vectors, containing a receptor subtype cDNA, a luciferase reporter gene under the control of the appropriate RXR response element, and secreted alkaline phosphatase (SEAP) gene as a background.
  • RXRa 0.5 e.q.
  • PPARy or LXRa 0.5 e.q.
  • partner response element 4 e.q.
  • COS-1 cells were transfected with QIA Effectene Transfection reagent according to the supplier's protocol.
  • Test compound solutions whose DMSO concentrations were below 1% were added to the suspension of transfected cells, which were seeded at about 4xl0 4 cells/mL in 96- well white plates.
  • Heterocycles 76, 137-142) solution in DMSO were added, respectively. After incubation in a humidified atmosphere of 5% CO2 at 37 °C for 18 h, some of the medium was used for SEAP and the remaining cells were used for luciferase reporter gene assays with a Steady-Glo Luciferase Assay system (Promega) according to the supplier' s protocol. The luciferase activities were normalized using secreted s.
  • reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine (50 mL) and added to silica gel ( ⁇ 5g). The mixture was concentrated to dryness under reduced pressure. Flash column chromatography (RediSepRf S1O2 (12 g), 100% hexanes ⁇ 10% EtOAc in hex .
  • BIOASSAY Assays for ABCAl and ABCGl Expression
  • Bioactivity of RXR agonist compounds as disclosed herein was assessed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of retinal pigment epithelium cells treated with specific compounds.
  • ARPE-19 cells a type of retinal pigment epithelium cell
  • DMEM maintenance medium
  • fetal bovine serum 10% fetal bovine serum

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Abstract

L'invention concerne des compositions et des méthodes pour le traitement d'une maladie oculaire, telle que la dégénérescence maculaire liée à l'âge. La composition peut renfermer un composé de formule (I) ou (II), ou un sel pharmaceutiquement acceptable de celui-ci. Le composé peut présenter à la fois une sélectivité pour un sous-type du récepteur RXR et la puissance d'un agoniste.
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US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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