Invented by Krzysztof Palczewski, Case Western Reserve University
The Case Western Reserve University invention works as followsA method for treating an ocular condition in a patient associated with an increased level of all-trans retina in an ocular tissues includes administering a therapeutically-effective amount of primary amine compounds of formula (I).nnand pharmaceutically-acceptable salts thereof.
Background for Compounds for treating ocular diseases
Visual pigments, which are highly expressed in rods and cones photoreceptors of the retina, are G-protein-coupled (GPCR) receptors. They consist of an opsin-apo-protein coupled with a universal color, 11-cisretinal, through a protonated Schiff-base. The retinylidene photochromophore undergoes photoisomerization to a trans configuration upon absorption of a light photon. This is followed by activation of photoreceptors. The opsin is released from all-trans retina by spontaneous hydrolysis of Schiff base bonds. However, because the visual pigments in the eye are packed tightly at local concentrations up to 5mM, a high-intensity stream of photons will produce all-trans retina. This aldehyde can be toxic at even very low concentrations. It primarily affects the photoreceptor cell.
This process is facilitated by two non-redundant enzymes, namely lecithin:retinol acyltransferase (LRAT) and retinoid isomerase, a retinal pigmented epithelium-specific 65 kDa protein (RPE65) (FIG. This process is facilitated through two non-redundant proteins, the lecithin-retinol-acyltransferase enzyme (LRAT), and the retinoid-isomerase protein, which is specific to retinal pigmented epithelium (RPE65). 1). Retinylamine is the first known potent RPE65 inhibitor. Both enzymes use retinylamine for their substrate. The LRAT produces retinylamine, which is then retained in the retina by LRAT.
An operational visual cycle is crucial for maintaining continuous vision and the health of photoreceptors cells. The homeostasis in retinoid metabolism is essential for maintaining visual function, regardless of the lighting condition. Nevertheless, environmental insults such as prolonged exposure to intense lighting in conjunction with an unfavorable genotype can overwhelm the adaptive abilities of the visual cycle. This compromises retinal function. A clinical example is Stargardt disease, an inherited form of juvenile macular degeneration that results in progressive vision loss associated with mutations in the photoreceptor-specific ATP binding cassette transporter (ABCA4) that causes a delay in all-trans-retinal clearance. The resulting increased concentrations of all-trans-retinal exert a direct cytotoxic effect on photoreceptors in addition to contributing to formation of side-products such as N-retinylidene-N-retinylethanolamine (A2E) and retinal dimer.
This application is a method and compound for treating an ocular disease in a patient with excessive or increased all-trans retinal levels in the subject’s ocular tissues. Ocular disorders can include retinal disorders such as macular degeneration including age-related, Stargardt’s disease and retinitis pigmentosa. The treatment of the ocular disease in a patient can include administering a therapeutically-effective amount of a compound of primary amine formula:
In one aspect of the application the primary amine compounds do not inhibit RPE65 enzyme activity or any other protein involved in retinoid metabolic in the eye of a subject. Primary amine compounds may reduce A2E formation and/or the retinal dimer and promote 11-cis retinal production in a subject’s eye. “The primary amine does not cause night blindness.
In another aspect of the invention, the primary compound amine can be administered to the subject in at least one way: topical application, systemic application, intravitreal injection and/or intraocular administration. The primary amine is provided as an ocular formulation for sustained delivery in one example.
For convenience, some terms used in the specification and examples are collected here. All technical and scientific words used in this document have the same meaning that would be understood by a person of ordinary skill within the field to which the application belongs, unless defined otherwise.
The articles?a?” “The articles?a????? and?an?? These words refer to either one or more (i.e. to at least one) of a grammatical object in the article. For example, what is an element? One element can be used to denote more than one element.
The terms “comprise” are used. ?comprising,? ?include,? ?including,? ?have,? The words?have,? The terms ‘including’ and?having? The words’such as’, ‘e.g. The terms?such as?, ‘e.g. ?Including? “The terms ‘including’ and ‘including but not limiting to? “Including but not limited to” and “including but not limited to” are interchangeable.
The term ‘or’ as used here should be understood to mean?and/or?, unless the context clearly indicates otherwise. As used in this document, the term ‘or’ should be understood as?and/or? unless context clearly indicates otherwise.
It is to be noted that some of the compounds in the application have asymmetric carbon atoms (chiral). As a result, it is understood that all isomers produced by such an asymmetry fall within the scope and application of the invention unless otherwise indicated. These isomers are obtained in a largely pure form using stereochemically controlled syntheses and classical separation techniques. “The compounds in this application can exist as stereoisomeric forms, and therefore be produced either as individual stereoisomers of mixtures.
The term “isomerism” refers to compounds that have identical molecular formulae but differ in the nature or sequence of bonding between their atoms, or in the arrangement of their atoms in space. The term “isomerism” refers to compounds with identical molecular formulae, but which differ in their nature or sequence of bonding or their arrangement of atoms in their space. Stereoisomers are isomers that differ in their arrangement of atoms in spatial space. Stereoisomers are classified as ‘diastereoisomers’ if they are not mirror-images of each other. Stereoisomers which are not superimposable mirror-images are called enantiomers or optical isomers. “A carbon atom that is bonded with four nonidentical substitutes is called a chiral center.
The term “chiral isomer” refers to a compound with at least one chiral center. Refers to a substance with at least one center chiral. It can exist as an individual enantiomer, or as a mixture. Racemic mixtures are mixtures that contain equal amounts of individual forms of opposite chirality. Compounds with more than one chiral centre have 2n?1 pairs of enantiomeric forms, where n is number of chiral centres. Compounds that have more than one chiral centre can exist either as an individual diastereomer, or as a mixture diastereomers. This is called a “diastereomeric combination”. Stereoisomers can be classified by their absolute configuration (R/S) when only one chiral centre is present. Absolute configuration is the spatial arrangement of substituents that are attached to a chiral centre. The sequence rule of Cahn Ingold Prelog is used to rank the substituents that are attached to the chiral centre. (Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. Cahn & Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).
The term “geometric isomers” refers to diastereomers that are a result of the hindered rotation about double bonds. Refer to diastereomers whose existence is due to hindered rotating about double bonds. The prefixes Z and E or cis/trans indicate whether the group is on the same side or opposite of the double bonds in the molecule, according to Cahn-Ingold Prelog rules.
The compounds and structures discussed in the application also include all their atropic isomers. ?Atropic isomers? Stereoisomer types in which the atoms are arranged differently. Atropic isomers are a result of a restriction in rotation due to the hindrance caused by large groups around a central bond. These atropic mixtures are usually found as atrop isomers. However, recent improvements in chromatography have made it possible to separate certain mixtures.
The term “crystal polymorphs” is used to describe the phenomenon. “Polymorphs” or ‘crystal polymorphs’ Crystal forms or polymorphs? Crystal structures are those in which the same compound (or salt, or solvate) can crystallize with different packing arrangements. Crystal forms are usually distinguished by their X-ray patterns, infrared spectrum, melting point, hardness of the crystal, optical properties and electrical properties. One crystal form may be dominant due to factors such as the crystallization rate, storage temperature and recrystallization solution. “Crystallization of the compound under different conditions can produce crystal polymorphs.
The term “derivative” refers to compounds with a core structure that is shared by all and which are then substituted as described in this document. All compounds with formula I, for example, are primary amines. They all share formula I.
The term “bioisostere” refers to a compound that is formed by the exchange of an atom or a group of atoms with another atomic or group of atoms, which are broadly similar. The term “bioisostere” refers to the compound that is formed by exchanging an atom, or a group, with another atom, or group, which is broadly similar. A bioisosteric substitution is designed to produce a compound that has similar biological properties as the parent compound. Bioisosteric substitutions can be either physicochemically- or topologically-based. Bioisosteres of carboxylic acids include acylsulfonimides (tetrazoles), sulfonates and phosphonates. Patani and LaVoie’s Chem. Rev. 96, 3147-3176 (1996).
The phrase “parenteral administration” is used to describe the process of administering medication by parenteral route. “The phrases ‘parenteral administration? “Injections and other modes of administration are not limited to enteral or topical administration. They include intravenous, intermuscular, intrapleural intrapericardial intraarterial intrathecal intracapsular intraorbital intracardiac intradermal intraperitoneal transtracheal subcutaneous subcuticular intraarticular subcapsular subarachnoid intraspinal intrastemal infusion and injection.
The term “treating” refers to inhibiting a disease, disorder or condition in a subject (e.g., impeding its progress) and relieving the disease, disorder or condition. Refers to preventing a disease or disorder from progressing in a person, or relieving it, such as by causing a regression. “Treating the disease or disorder includes alleviating at least one of its symptoms, even if it does not affect the underlying pathophysiology.Click here to view the patent on Google Patents.