CN111527097A - Seleno galactoside compounds for treating systemic insulin resistance disorder and uses thereof - Google Patents
Seleno galactoside compounds for treating systemic insulin resistance disorder and uses thereof Download PDFInfo
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- CN111527097A CN111527097A CN201880083771.8A CN201880083771A CN111527097A CN 111527097 A CN111527097 A CN 111527097A CN 201880083771 A CN201880083771 A CN 201880083771A CN 111527097 A CN111527097 A CN 111527097A
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- heteroaryl
- naphthyl
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/08—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium
Abstract
Various aspects of the present invention are directed to novel synthetic compounds having binding affinity to galectin proteins for the treatment of systemic insulin resistance disorders.
Description
Inventor(s):
p G Talbot, E Zoommer, D Slider, J M Johnson, R George, S Schektel and R Neille.
RELATED APPLICATIONS
This application claims the benefit and priority of U.S. provisional application serial No. 62/579,343, filed on 31/10/2017, the entire disclosure of which is incorporated herein by reference in its entirety.
Technical Field
Various aspects of the invention relate to compounds, pharmaceutical compositions, methods for making compounds, and methods for treating metabolic disorders mediated at least in part by one or more galactose binding proteins, also known as galectins.
Background
Galectins are a family of S-type lectins that bind glycoproteins that contain β -galactosan. To date, 15 mammalian galectins have been isolated. Galectins regulate different biological processes such as diabetes, inflammation, fibrogenesis, metabolic disorders, cancer progression, metastasis, apoptosis and immune evasion.
Disclosure of Invention
Various aspects of the present invention relate to compounds and compositions for use in therapeutic formulations (the compositions comprising the compounds in an acceptable pharmaceutical carrier) for parenteral or enteral administration. In some embodiments, the composition may be administered orally or topically (topically) or parenterally via intravenous or subcutaneous routes.
Aspects of the present invention relate to compounds, compositions, and methods for treating various disorders, including but not limited to the treatment of systemic insulin resistance, in which lectin proteins play a role in the pathogenesis of various disorders. In some embodiments, the compounds can reverse galectin-3binding to insulin receptors and/or enhance sensitivity to insulin activity in various tissues.
Various aspects of the present invention relate to compounds, compositions and methods for the treatment of (but not limited to) systemic insulin resistance. In some embodiments, systemic insulin resistance is associated with obesity, in which case elevated galectin-3 interacts with the insulin receptor. In some embodiments, treatment with the compounds of the present invention may restore sensitivity to insulin activity in various tissues.
Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 1 diabetes. Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 2 diabetes (T2 DM). Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores sensitivity of the cell to insulin activity. In some embodiments, the compounds inhibit galectin-3 interaction with insulin receptors, which interferes with insulin binding and cellular glucose uptake mechanisms. Various aspects of the present invention relate to compounds, compositions and methods for treating low grade (low grade) inflammation caused by elevated free fatty acid and triglyceride levels that cause insulin resistance in skeletal muscle and liver, leading to the development of atherosclerotic vascular disease and NAFLD. Various aspects of the invention relate to compounds, compositions and methods for treating polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance and compensatory hyperinsulinemia. Various aspects of the present invention relate to compounds, compositions and methods for treating diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGF β receptor pathways (pathways) in chronic kidney disease. In some embodiments, the compounds may inhibit the overexpression of the TGF β receptor signaling (signaling) system triggered by insulin resistance in diabetic patients (diabetic) and cause reduced renal function, and may reverse the proven (estableshed) pathology of diabetic glomerulopathy.
In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with one or more antidiabetic drugs. In some embodiments, administration of a compound of the invention and an active agent produces a synergistic effect.
Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, where elevated galectin-3 interacts with insulin receptors. In some embodiments, treatment with the compounds of the present invention may restore sensitivity to insulin activity in various tissues.
In some embodiments, the compounds or compositions of the invention bind to the insulin receptor (also known as IR, INSR, CD220, HHF 5).
Various aspects of the invention relate to compounds, compositions and methods for treating diseases caused by disruption of TGFb1 (transforming growth factor β 1) activity.
Various aspects of the invention relate to compounds, compositions and methods for treating diseases associated with the transforming growth factor beta signaling pathway.
Various aspects of the invention relate to compounds or compositions for the treatment of various chronic inflammatory diseases, fibrotic diseases and cancers. In some embodiments, the compounds are capable of mimicking the interaction of glycoproteins with lectin or galectin proteins, which are known to modulate pathophysiological pathways leading to immune recognition, inflammation, fibrosis, angiogenesis, cancer progression and metastasis.
In some embodiments, the compounds include pyranosyl and/or furanosyl structures bound to the selenium atom at the anomeric carbon (anomeric carbon) of the pyranosyl (pyranosyl) and/or furanosyl (furanosyl).
In some embodiments, specific aromatic substitutions may be added to the galactose core or heteroside core to further enhance the affinity of the selenium bound (selenium bound) pyranosyl and/or furanosyl structure. Such aromatic substitutions may enhance the interaction of the compound with amino acid residues (e.g., arginine, tryptophan, histidine, glutamic acid, etc.) that make up the Carbohydrate Recognition Domain (CRD) of the lectin, and thus enhance association (association) and binding specificity.
In some embodiments, the compound may include a monosaccharide, disaccharide, oligosaccharide of galactose, or heteroside core bound to a selenium atom (Se) on the anomeric carbon of galactose or heteroside.
In some embodiments, the compound is a symmetrical digalactoside (digalactoside), wherein the two galactosides are joined by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, wherein both galactosides are bound by one or more selenium linkages, and wherein selenium is bound to the anomeric carbon of galactose. In some embodiments, the compound is a symmetric digalactoside, wherein both galactosides are bound by one or more selenium bonds and one or more sulfur bonds (sulfur bonds), and wherein selenium is bound to the anomeric carbon of galactose. In other embodiments, the compound may be an asymmetric digalactoside. For example, the compounds may have different aromatic or aliphatic substitutions on the galactose core.
In some embodiments, the compound is a symmetrical galactoside having one or more selenium on the anomeric carbon of galactose. In some embodiments, the galactoside has one or more selenium bound to the galactose anomeric carbon and one or more sulfur bound to the selenium. In some embodiments, the compounds may have different aromatic or aliphatic substitutions on the galactose core.
Without being bound by theory, it is believed that the selenium molecule containing compound stabilizes the metabolism of the compound while maintaining the chemical, physical and allosteric properties of specific interactions with lectins or galectins known to recognize carbohydrates.
In some embodiments, the galactosyl mono-, di-, or oligosaccharides of the galactose of the present invention are metabolically more stable than compounds having an O-or S-glycosidic linkage.
In some embodiments, the compound is a compound having formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof:
wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, SO3, PO2, amino acids, heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein R is1、R2And R3Independently selected from CO, O2, SO2, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxyl group, an alkenyl of at least 3 carbons substituted with a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxyl group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxyl group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxyl group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, or a combination of theseA phenyl group substituted by at least one nitro group, a phenyl group substituted by at least one sulfo group, a phenyl group substituted by at least one amino group, a phenyl group substituted by at least one alkylamino group, a phenyl group substituted by at least one dialkylamino group, a phenyl group substituted by at least one hydroxyl group, a phenyl group substituted by at least one carbonyl group and a phenyl group substituted by at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted by at least one carboxyl group, a naphthyl group substituted by at least one halogen group, a naphthyl group substituted by at least one alkoxy group, a naphthyl group substituted by at least one nitro group, a naphthyl group substituted by at least one sulfo group, a naphthyl group substituted by at least one amino group, a naphthyl group substituted by at least one alkylamino group, a naphthyl group substituted by at least one dialkylamino group, a naphthyl group substituted by at least one hydroxyl group, a naphthyl group substituted by at least one carbonyl group and a naphthyl group substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted with at least one carboxyl group, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one alkoxy group, heteroaryl substituted with at least one nitro group, heteroaryl substituted with at least one sulfo group, heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) a saccharide, a substituted saccharide, D-galactose, a substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
In some embodiments, the compound has general formula (3) or formula (4) or a pharmaceutically acceptable salt or solvate thereof:
wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substitutions having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, SO2, PO2 and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein n is less than or equal to 24,
wherein R is1And R2Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxyl group, an alkenyl of at least 3 carbons substituted with a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxyl group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxyl group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxyl group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, or a pharmaceutically acceptable salt thereof, Heteroaryl substituted by at least one nitro group, by at least oneHeteroaryl substituted with sulfo groups, heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) a saccharide, a substituted saccharide, D-galactose, a substituted D-galactose, C3- [1,2,3]]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino. In some embodiments, n ═ 1. In other embodiments, n is 3.
In some embodiments, the compound is a compound having formula (5) or formula (6), or a pharmaceutically acceptable salt or solvate thereof:
wherein X is Se, Se-S, S-Se, Se-SO2 or SO2-Se,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein R is1、R2、R3And R4Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxyl group, an alkenyl of at least 3 carbons substituted with a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group and a carboxyl groupAlkenyl of at least 3 carbons substituted by both radicals and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxy group, phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy group, phenyl substituted by at least one nitro group, phenyl substituted by at least one sulfo group, phenyl substituted by at least one amino group, phenyl substituted by at least one alkylamino group, phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxy group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxy group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, Naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, D) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen, heteroaryl substituted by at least one alkoxy group, heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, heteroaryl substituted by at least one amino group, heteroaryl substituted by at least one alkylamino group, heteroaryl substituted by at least one dialkylamino group, heteroaryl substituted by at least one hydroxyl group, heteroaryl substituted by at least one carbonyl group and heteroaryl substituted by at least one substituted carbonyl group, and e) sugars, substituted sugars, D-galactose, Substituted D-galactose, C3- [1,2,3]]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
In some embodiments, halogen is a fluoro, chloro, bromo, or iodo group.
In some embodiments, the compound is a 3-derivatized diselenogenaglycoside (3-derivitized diselenogenaglycoside) bearing fluorophenyl triazole.
Various aspects of the present invention relate to compounds of formula (5) or a pharmaceutically acceptable salt or solvate thereof:
in some embodiments, the compound is in free form. In some embodiments, the free form is an anhydrate (anhydride). In some embodiments, the free form is a solvate, such as a hydrate.
In some embodiments, the compound is in a crystalline form.
Some aspects of the invention relate to pharmaceutical compositions comprising a compound of the invention and optionally a pharmaceutically acceptable additive, such as an adjuvant, carrier, excipient, or combination thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable additive, such as an adjuvant, carrier, excipient, or a combination thereof.
In some embodiments, the compounds of the invention bind to one or more galectins. In some embodiments, the compound binds to galectin-3, galectin-1, galectin 8 and/or galectin 9.
In some embodiments, the compounds of the invention have high selectivity and affinity for galectin-3. In some embodiments, the compounds of the invention have an affinity for galectin-3 of about 1nM to about 50. mu.M.
Various aspects of the invention relate to compositions or compounds that may be used to treat diseases. Various aspects of the invention relate to compositions or compounds that may be used to treat diseases in which galectins are at least partially implicated in pathogenesis. Other aspects of the invention relate to methods of treating a disease in a subject in need thereof.
Some aspects of the present invention relate to a method of treating insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof.
Some aspects of the invention relate to methods of treating insulin resistance comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the compounds may be used in combination with an active agent. In some embodiments, the active agent is an immunomodulator, an anti-inflammatory drug, a vitamin, a nutraceutical, a supplement, or a combination thereof. In some embodiments, administration of a compound of the invention and an active agent produces a synergistic effect.
Some aspects of the invention relate to methods of treating diseases caused by disruption of the activity of TGF β 1 (transforming growth factor β 1), which restore normal regenerative activity in tissues by reversing galectin-3 interaction with its receptor (TGF β 1-receptor).
Some aspects of the invention relate to methods of treating diseases associated with the transforming growth factor beta signaling pathway involving many cellular and pathological processes in both adult and embryonic development, including cell growth, cell differentiation, apoptosis, cellular homeostasis, and other cellular functions.
Some aspects of the invention relate to methods for treating a disorder associated with galectin binding, such as galectin-3binding to insulin receptor or TGF β 1-receptor in humans, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (1), (2), (3), (4), (5), (6), or (7).
Some aspects of the invention relate to a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a disorder associated with binding of galectins in a subject in need thereof. Some aspects of the invention relate to a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a disorder associated with the binding of galectin-3and a ligand in a subject in need thereof.
In some embodiments, the subject in need thereof is a mammal. In some embodiments, the subject in need thereof is a human.
Some aspects of the present invention relate to methods for treating a disorder associated with the binding of a galectin, such as galectin-3, to a ligand in a human, wherein the method comprises administering to the human in need thereof a therapeutically effective amount of at least one compound of formula (1), (2), (3), (4), (5), (6) or (7), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treatment is for systemic insulin resistance.
Drawings
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the office upon request and payment of the necessary fee.
The present invention will be further explained with reference to the appended figures, wherein like structure is referred to by like numerals throughout the several views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
Figure 1 depicts the high resolution 3D structure of the galectin-3 Carbohydrate Recognition Domain (CRD) binding pocket (binding pocket) with 3 potential interaction sites.
Figure 2 depicts the CRD pocket location in the C-terminus of galectin-3 with bound lactose units.
FIG. 3 depicts a map of potential synergistic amino acids near the site of galectin-3 CRD for enhanced binding.
Fig. 4 depicts the synthesis of selenalactoside compounds according to some embodiments.
FIG. 5A depicts a fluorescence Polarization Assay method (fluorescence Polarization Assay Format) to detect compounds that specifically bind to CRD according to some embodiments.
Fig. 5B depicts a fluorescence resonance energy transfer assay (FRET method) (e.g., TGFb 1-acceptor FRET method) for screening compounds that inhibit galectin-3 interaction with its glycoprotein-ligand according to some embodiments.
Fig. 6A depicts inhibition of galectin binding moieties using a specific anti-galectin-3 monoclonal antibody binding assay (ELISA method), according to some embodiments.
Figure 6B depicts a functional assay (e.g., an insulin-receptor ELISA method) according to some embodiments that screens compounds that inhibit galectin-3 interaction with its glycoprotein-ligand.
Figure 7 provides an example of compound IC50 by fluorescence polarization-CRD specific assay of the compound according to some embodiments.
Figure 8 provides an example of compound IC50 as determined by the insulin-receptor-galectin-3 ELISA method according to some embodiments.
Figure 9 provides an example of compound IC50 as determined by TGFb 1-receptor-galectin-3 ELISA method according to some embodiments.
Detailed Description
Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. Furthermore, each of the examples given in connection with the various embodiments of the invention are intended to be illustrative, and not restrictive. The figures are not necessarily to scale; some features may be exaggerated to show details of particular components. Further, any measurements, specifications, and the like shown in the figures are illustrative and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.
Citation of a document herein is not intended as an admission that any of the documents cited herein are pertinent prior art, or that the cited documents are considered important to the patentability of the claims of the present application.
Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases "in one embodiment" and "in some embodiments" as used herein do not necessarily refer to the same embodiment, although they may. Moreover, the phrases "in another embodiment" and "in some other embodiments" as used herein do not necessarily refer to a different embodiment, although they may. Thus, as described below, various embodiments of the invention may be readily combined without departing from the scope or spirit of the invention.
Further, as used herein, the term "or" is an inclusive "or" operator, and is equivalent to the term "and/or," unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for additional factors not described, unless the context clearly dictates otherwise. Furthermore, throughout the specification, the meaning of "a", "an" and "the" includes plural references.
All percentages expressed herein are weight/weight unless otherwise indicated.
Various aspects of the present invention relate to compositions of mono-, di-and oligosaccharides of a galactose (or heteroside) core bound to a selenium atom (Se) at the anomeric carbon of galactose (or heteroside). In some embodiments, Se-containing molecules render them metabolically stable while maintaining the chemical, physical, and allosteric properties of specific interactions with lectins known to recognize carbohydrates. In some embodiments, the specific aromatic substitution added to the galactose core further enhances the affinity of the selenium-bound pyranosyl and/or furanosyl structure by: enhance their interaction with the amino acid residues (e.g., arginine, tryptophan, histidine, glutamic acid, etc.) of the Carbohydrate Recognition Domain (CRD) that makes up the lectin, and thus enhance association and binding specificity.
In some embodiments, the compositions or compounds may be used to treat non-alcoholic steatohepatitis, inflammatory and autoimmune disorders, neoplastic disorders, or cancer with or without liver fibrosis.
In some embodiments, the composition may be used to treat liver fibrosis, kidney fibrosis, lung fibrosis, or cardiac fibrosis.
In some embodiments, the composition or compound is capable of enhancing anti-fibrotic activity in an organ (including but not limited to liver, kidney, lung, and heart).
In some embodiments, the compositions or compounds may be used to treat inflammatory disorders of the vasculature, including atherosclerosis and pulmonary hypertension.
In some embodiments, the compositions or compounds may be used to treat cardiac disorders, including heart failure, cardiac arrhythmias, and uremic cardiomyopathy.
In some embodiments, the compositions or compounds may be used to treat kidney diseases, including glomerulopathy and interstitial nephritis.
In some embodiments, the compositions or compounds may be used to treat inflammatory, proliferative, and fibrotic skin disorders, including but not limited to psoriasis and scleroderma.
Various aspects of the invention relate to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis or asthma.
Various aspects of the invention relate to methods of treating inflammatory and fibrotic disorders in which galectins are involved at least in part in their pathogenesis by enhancing anti-fibrotic activity in organs including, but not limited to, the liver, kidney, lung and heart.
Various aspects of the invention relate to methods, compositions, or compounds having therapeutic activity for the treatment of non-alcoholic steatohepatitis (NASH). In other aspects, the invention relates to methods of reducing the pathology and disease activity associated with non-alcoholic steatohepatitis (NASH).
Various aspects of the invention relate to compositions or compounds for treating or methods of treating inflammatory and autoimmune disorders in which galectins are involved, at least in part, in the pathogenesis of the disorder, including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
Various aspects of the invention relate to compositions or compounds for treating neoplastic disorders (e.g., benign or malignant neoplastic diseases) in which galectins are implicated, at least in part, in pathogenesis, by inhibiting processes facilitated by the increase in galectins. In some embodiments, the present invention relates to methods of treating neoplastic disorders (e.g., benign or malignant neoplastic diseases) in which galectins are involved, at least in part, in pathogenesis, by inhibiting processes facilitated by the increase in galectins. In some embodiments, the compositions or compounds can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the compositions or compounds may be used to treat primary and secondary cancers.
Various aspects of the invention relate to compositions or compounds for the treatment of neoplastic disorders in combination with other antineoplastic agents, including but not limited to checkpoint inhibitors (anti-CTLA 2, anti-PD 1, anti-PDL 1), other immunomodulators (including but not limited to anti-OX 40), and a variety of other antineoplastic agents of various mechanisms.
In some embodiments, a therapeutically effective amount of a compound or composition may be compatible and effectively combined with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other drugs and nutraceuticals or supplements, or combinations thereof and the like.
Galectins
Galectins (also known as galectins or S-lectins) are a family of lectins that bind to beta-galactosides. Galectins, a common name for the animal lectin family, were proposed in 1994 (Barondes, S.H., et al: Galectins: animal beta-galactoside-binding lectin family (Galectins: a family of animal beta-galactoside-binding lectins): cell 76, 597-598, 1994). This family is defined by having at least one characteristic Carbohydrate Recognition Domain (CRD) with affinity for β -galactosides and sharing certain sequence elements. Further structural characterization divided galectins into three subgroups, including: (1) galectins with a single CRD, (2) galectins with two CRDs connected by a connecting peptide, and (3) groups with one member (galectin-3), galectin-3 having one CRD connected to a different type of N-terminal domain. The galectin carbohydrate recognition domain is a beta-sandwich (sandwish) of about 135 amino acids. The two sheets (sheet) are slightly curved with 6 chains forming concave sides, also called S-sides, and 5 chains forming convex sides, F-sides). The concave side forms a recess into which carbohydrates are bound (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). "Introduction to galectins" J.Saccharoconj.19 (7-9): 433-40).
Various biological phenomena have been shown to be associated with galectins, including development, differentiation, morphogenesis, tumor metastasis, apoptosis, RNA splicing, etc.
Typically, the carbohydrate domain binds to galactose residues associated with glycoproteins. Galectins show affinity for attachment to galactose residues of other organic compounds, such as in fragments of lactose [ (beta-D-galactoside) -D-glucose ], N-acetyl-lactosamine, poly-N-acetyllactosamine, galactomannan or pectin. However, it should be noted that galactose itself does not bind to galectins.
Based on the presence of galactose containing residues in the macromolecular background, it was suggested that plant polysaccharides if gums and modified pectins bind to galectin proteins, in this case complex carbohydrates, rather than glycoproteins in the case of animal cells.
At least 15 mammalian galectin proteins have been identified which have one or two carbohydrate domains in tandem.
Galectin proteins are present in the intercellular space where they are endowed with many functions, while they are also secreted into the extracellular space with different functions. In the extracellular space, galectin proteins may have a variety of functions mediated by their interaction with galactose-containing glycoproteins, including facilitating interactions between glycoproteins that may regulate functions, or, in the case of integral membrane glycoprotein receptors, regulating cell signaling (Sato et al, galectin as a danger signal in host-pathogen and host-tumor interactions: "siren" growing new members (Galectins as signal in host-pathway and host-tumor interactions), "Galectins" (Klyosov et al, John Wiley and Sons),115-145, 2008; Liu et al, Galectins in acute and chronic inflammation, new york academy of sciences annual book (ann.n.y.acad.sci.), 1253: 80-91, 2012). Galectin proteins in the extracellular space may also promote cell-cell and cell matrix interactions Wang et al, Nuclear and cytoplasmic localization of galectin-1and galectin-3and their role in precursor mRNA splicing ("galectin" (Klyosov et al), John Wiley and Sons, 87-95, 2008). With respect to the intracellular space, galectin function appears to be more related to protein-protein interactions, but intracellular vesicle trafficking appears to be related to glycoprotein interactions.
Galectins have been shown to have domains that promote homodimerization. Thus, galectins can act as "molecular glue" between glycoproteins. Galectins are present in a number of cellular compartments, including the cell core and cytoplasm, and are secreted into the extracellular space, where they interact with cell surfaces and extracellular matrix glycoproteins. The mechanism of molecular interaction depends on the location. While galectins can interact with glycoproteins in the extracellular space, the interaction of galectins with other proteins in the intracellular space typically occurs via protein domains. In the extracellular space, association of cell surface receptors may increase or decrease the ability of the receptors to signal or interact with ligands.
Galectin proteins are significantly increased in a number of animal and human disease states, including but not limited to disorders associated with inflammation, fibrosis, autoimmunity and neoplasia. Galectins have been directly implicated in disease pathogenesis, as described below. For example, disease states that may depend on galectins include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic disorders, asthma, dermatitis, autoimmune diseases, inflammatory and degenerative arthritis, immune-mediated neurological diseases, fibrosis of multiple organs (including but not limited to liver, lung, kidney, pancreas and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular inflammatory diseases, various cancers.
In addition to disease states, galectins are important regulatory molecules in modulating immune cell responses to vaccination, foreign pathogens, and cancer cells.
One skilled in the art will appreciate that compounds that can bind to galectins and/or alter the affinity of galectins for glycoproteins, reduce heterotypic or homotypic interactions between galectins, or otherwise alter the function, synthesis, or metabolism of galectin proteins may have important therapeutic effects in galectin-dependent diseases.
Galectin proteins, such as Galectin-1and Galectin-3, have been shown to significantly increase in inflammation, fibrotic disorders and neoplasia (Ito et al, Galectin-1as an effective target for Cancer therapy: role in tumor microenvironment for Cancer therapy ("Galectin-1 as a potential target for Cancer therapy"), Cancer Metastasis Rev.PMID: 22706847(2012), Nangia-Makker et al, Galectin-3binding and Metastasis (Galectin-3binding and Metastasis), "molecular biology Methods" (Methods mol. Biol. 251.: 878: 266, 2012, Cancer et al, expression of Galectin-3 is associated with the progression and clinical outcome of bladder Cancer (Galectin-3expression syndrome) and tumor formation (tumor biology, Cancer et al, Galectin-3expression is associated with bladder Cancer progression and clinical outcome of tumors (tumor-3 expression syndrome, Cancer tumor tissue and tumor tissue, Cancer tumor tissue infection, Cancer tumor growth, Cancer Metastasis, Cancer, 31: 277-285, 2010, Wanninger et al, alcoholic cirrhosis patients with elevated Systemic and hepatic venous galectin-3 levels and negative correlation with liver function (Systemic and hepatic vascular galectin-3are involved in hepatic dysfunction with intracellular Cytokine with liver function), "cytokines (cytokines), 55: 435-40, 2011). Furthermore, experiments have shown that galectins, in particular Galectin-1 (gal-1) and Galectin-3 (gal-3), are directly involved in the pathogenesis of these diseases (Toussaint et al, Galectin-1 gene is preferentially expressed at the Tumor margins, promoting glioblastoma cell infiltration ("Galectin-1, a gene expressed at the Tumor margin"), mol.cancer.11: 32, 2012; Liu et al, 2012, Newlzyl et al, Galectin-3-a universal killer of Cancer ("Galectin-3-a jam-of-all-around-Cancer"), Cancer Lett.313: 123- -, cancer research (Cancer Res), 71: 4423-31, 2011; lefranc et al, Galectin-1mediated biochemical control of melanoma and glioma invasion behavior ("Galectin-1 mediated biochemical control of melanoma and glioma modify beauveor"), [ journal of World biochemistry (World J.biol.chem.), 2: 193-201, 2011, Forsman et al, Galectin3aggravates inflammation and destruction of joints in antigen-induced Arthritis, ("Galectin 3 aggrevates joint inflammation and destruction in anti-inflammatory-induced Arthritis"), (Arthritis and rheumatism), 63: 445, 454, 2011; de Boer et al, Galectin-3, and cardiac remodeling and heart failure ("Galectin-3 in cardiac remodelling and heart failure"), curr. Ueland et al, galectin-3in heart failure: high levels correlate with all-cause mortality ("Galectin-3 in heart failure with all-cause mortality"), journal of international cardiology (Int j. heart), 150: 361-364, 2011; ohshima et al, role of Galectin 3and its binding proteins in rheumatoid Arthritis ("Galectin 3and its binding protein in rhematoid Arthritis"), Arthritis and rheumatism (Arthritis Rheum.), 48: 2788-2795, 2003).
High levels of serum galectin-3 have been shown to be associated with certain human diseases, such as a more aggressive form of heart failure, making the identification of high risk patients using galectin-3 detection an important component of patient care. Galectin-3 detection can be used to help physicians determine which patients are at higher risk of hospitalization or death. For example, BGMThe test is an in vitro diagnostic device that can quantitatively measure galectin-3in serum or plasma and can be used in conjunction with clinical evaluation to help evaluate the prognosis of patients diagnosed with chronic heart failure. Measurement of endogenous protein galectin-3 concentration can be used to predict or monitor disease progression or treatment efficacy in patients receiving cardiac resynchronization therapy (see US 8,672,857).
Galectin-3 has been shown to be elevated in patients with metabolic disorders and obese people with diabetes associated with systemic insulin resistance. High levels of serum galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a persistent disease that can be resolved or carefully prevented. It is one of the most common metabolic syndromes in the world. Diabetes is primarily associated with the central and peripheral nervous systems and is a chronic complication. Diabetes is a common metabolic syndrome of diabetes, and the body cannot use glucose and stores it in the blood, possibly damaging the kidneys, nerves, heart, eyes and causing other complications.
Insulin resistance
Insulin resistance is a characteristic manifestation of patients with diabetic (T2DM) complications and is one of the defining clinical features of metabolic syndrome (MetS). MetS is a group of biochemical and metabolic diseases estimated to affect more than 20% of adults (> 20 years) or approximately 5 billion americans in the united states. This figure may rise dramatically in the future since the prevalence of obesity shows no sign of reversion.
The main feature of type 2 diabetes, insulin resistance, may develop in people with type 1 diabetes, clinically designated as dual diabetes. People with dual diabetes always have type 1 diabetes, but are accompanied by complications of insulin resistance. The most common cause of developing insulin resistance is obesity, and type 1 diabetes itself is not caused by obesity.
Insulin is a hormone that has multiple functions, including facilitating transport of nutrients into cells, regulating various enzymatic activities, and regulating energy homeostasis. These functions involve glucose metabolism in the liver, adipose tissue and muscle through intracellular signaling pathways. In the liver, insulin resistance leads to increased hepatic glucose production. In adipose tissue, insulin resistance affects lipase activity, resulting in antilipidemic effects, affecting free fatty acid flow out of adipocytes, increasing circulating free fatty acids.
Recent studies have shown that galectin-3 plasma levels are significantly elevated in human and animal obesity models.
It has been reported that in obesity, macrophages and other immune cells are recruited to insulin target tissues and contribute to chronic inflammatory states and insulin resistance. Galectin-3, which is known to be secreted mainly by macrophages, may play a key role in this inflammatory process, and thus it links inflammation to a decrease in insulin sensitivity.
The insulin receptor is a transmembrane protein activated by bound insulin, IGF-I, IGF-II, and belongs to the class of tyrosine kinase receptors. Insulin receptors play a key role in regulating glucose homeostasis when dysfunction or metabolic disorders may lead to a range of clinical manifestations, including but not limited to diabetes. The insulin receptor is encoded by the single gene, INSR, and may result in the IR-A or IR-B subtypes during transcription. These post-translational isomers lead to the formation of proteolytic alpha and beta subunits, which combine to form the transmembrane insulin receptor with a final activity ≈ 320 kDa.
The interaction of the insulin receptor and insulin is the checkpoint for the second pathway, Ras-mitogen-activated protein kinase (MAPK), which mediates gene expression, and also influences the PI3K-AKT pathway that controls cell growth and differentiation. Insulin Receptor Substrates (IRS) are common intermediates, including four different family members IRS 1-4. Defects in insulin signaling often involve insulin receptor substrate-1 (IRS 1). Activation of the insulin receptor increases tyrosine phosphorylation of IRS1, thereby initiating signal transduction. However, when serine 307 is phosphorylated, signaling is reduced. Other negative regulators associated with inflammation of IR or IRs1, including cytokine signaling inhibitors (Socs), may promote ubiquitination, in which ubiquitin (a small protein) binds to another target protein, alters its function and subsequently degrades, e.g., IRs inactivation.
Some aspects of the invention relate to compounds and uses of compounds that inhibit galectin-3 to treat insulin resistance.
Galectin inhibitors
Natural oligosaccharide ligands capable of binding galectin-1 and/or galectin-3 have been described, for example modified forms of pectin and galactomannan derived from guar gum (see WO 2013040316, US20110294755, WO 2015138438). Synthetic digalactosides such as lactose, N-acetyllactosamine (LacNAc) and thiolactose that are effective against pulmonary fibrosis and other fibrotic diseases (WO 2014067986 a1, which is incorporated herein by reference in its entirety).
The development of protein crystallography and the availability of high definition 3D structures for the Carbohydrate Recognition Domain (CRD) of many galectins has resulted in a number of enhanced affinity derivatives with greater affinity for carbohydrate recognition domains than galactose or lactose (WO 2014067986, incorporated herein by reference in its entirety). These compounds have proven to be effective in the treatment of an animal model of pulmonary fibrosis, which is believed to mimic human Idiopathic Pulmonary Fibrosis (IPF). For example, thio-digalactopyranosyl (TD-139) substituted with a 3-fluorophenyl-2, 3-triazolyl group has been reported to bind to galectin 3and to be effective in a mouse model of pulmonary fibrosis. The compounds require pulmonary administration using an intratracheal instillation or nebulizer (see US 8703720, US 7700763, US 7638623, and US 7230096, the entire contents of which are incorporated herein by reference).
Various aspects of the present invention relate to novel compounds that mimic the natural ligands of galectin proteins. In some embodiments, the compound mimics a natural ligand of galectin-3. In some embodiments, the compound mimics a natural ligand of galectin-1. In some embodiments, the compound mimics a natural ligand of galectin-8. In some embodiments, the compound mimics a natural ligand of galectin-9.
In some embodiments, the compound has a mono-, di-, or oligomeric structure consisting of a galactose-selenium core bound to an isomeric carbon on galactose, and which serves as a linking group for the rest of the molecule. In some embodiments, the galactose-selenium core may bind to other sugars/amino acids/groups that bind to galectin CRD (as shown in fig. 1 in the high definition 3D structure of galectin-3), and together may enhance the affinity of the compound for CRD. In some embodiments, the galactose-selenium core may bind to other sugars/amino acids/groups that bind to "site B" of galectin CRD (as shown in fig. 1 in the high definition 3D structure of galectin-3), and together may enhance the affinity of the compound for CRD.
According to some aspects, the compounds may have substitutions that interact with site a and/or site C to further improve binding to CRD and enhance its potential as a therapeutic agent targeting galectin-dependent pathologies. In some embodiments, substituents may be selected by in silico analysis (computer-assisted molecular model construction) as described herein. In some embodiments, substituents may be further screened using a binding assay with a galectin protein of interest. For example, compounds can be screened using an in vitro inflammatory and fibrotic model of galectin-3binding assays and/or activated cultured macrophages (see Chavez-Galan, L et al, immunology 2015; 6: 263).
According to some aspects, the compound comprises one or more specific substitutions of core galactose-Se. For example, the core galactose-Se may be substituted with specific substituents that interact with residues located within the CRD. Such substituents can significantly increase the association and potential potency of the compounds as well as the 'druggability' characteristics.
Selenium
Selenium has five possible oxidation states (-2, 0, +2, +4, and +6) and therefore performs well in a variety of compounds with different chemical properties. In addition, almost all sulfur-containing compounds, whether inorganic or organic, can be substituted for sulfur with selenium.
Most organic and inorganic selenium compounds are readily absorbed from the diet and transported to the liver, the major organ of selenium metabolism. The general metabolism of selenium compounds follows three main pathways, depending on the chemical properties, i.e. redox active selenium compounds, precursors of methyl selenol and seleno-amino acids.
Selenium is generally considered an antioxidant because it is present in selenoprotein in the form of selenocysteine, but may also be toxic. However, the toxic effects of selenium are strictly concentration and chemical species dependent. One class of selenium compounds is a potent cytostatic agent with significant tumor specificity (Misra, 2015). Sodium selenite has been studied as a cytotoxic drug in advanced cancers (SECOR, see Brodin, Ola et al, 2015).
Galactoside-selenium compound
Various aspects of the present invention relate to compounds comprising a pyranosyl and/or furanosyl structure bound to a selenium atom at the anomeric carbon of the pyranosyl and/or furanosyl group.
In some embodiments, specific aromatic substitutions may be added to the galactose core or heteroside core to further enhance the affinity of the selenium-bound pyranosyl and/or furanosyl structure. Such aromatic substitutions may enhance the interaction of the compound with amino acid residues (e.g., arginine, tryptophan, histidine, glutamic acid, etc.) of the Carbohydrate Recognition Domain (CRD) that makes up the lectin, and thus enhance association and binding specificity.
In some embodiments, the compound comprises mono-, di-, and oligosaccharides of galactose or a heteroside core bound to a selenium atom on the anomeric carbon of galactose or a heteroside.
In some embodiments, the compound is a symmetrical digalactoside, wherein both galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, wherein both galactosides are bound by one or more selenium linkages, and wherein selenium is bound to the anomeric carbon of galactose. In some embodiments, the compound is a symmetric digalactoside, wherein both galactosides are bound through one or more selenium bonds and one or more sulfur bonds, and wherein selenium is bound to the anomeric carbon of galactose. In other embodiments, the compound may be an asymmetric digalactoside. For example, the compounds may have different aromatic or aliphatic substitutions on the galactose core.
In some embodiments, the compound is a symmetrical galactoside, which is a monogalactoside with one or more selenium on the anomeric carbon of galactose. In some embodiments, the galactoside has one or more selenium bound to the anomeric carbon of galactose and one or more sulfur bound to selenium. In some embodiments, the compounds may have different aromatic or aliphatic substitutions on the galactose core.
Without being bound by theory, it is believed that compounds comprising Se-containing molecules stabilize the metabolism of the compound while maintaining the chemical, physical and allosteric properties of specific interactions with lectins or galectins known to recognize carbohydrates. In some embodiments, the galactoside digalactoside or oligosaccharide of galactose of the present invention is metabolically more stable than compounds having an O-glycosidic bond.
In some embodiments, the galactoside or oligosaccharide of galactose of the present invention is metabolically more stable than compounds having an S-glycosidic bond.
Various aspects of the present invention relate to compounds based on galactoside structures having a selenium bridge [ X ] with another galactose, hydroxycyclohexane, aromatic moiety, alkyl, aryl, amine or amide.
As used herein, the term "alkyl" is meant to include 1 to 12 carbon atoms, such as 1 to 7 or 1 to 4 carbon atoms or 3 to 7 carbon atoms. In some embodiments, the alkyl group may be straight or branched. In some embodiments, the alkyl group may also form a ring comprising 3 to 7 carbon atoms, preferably 3, 4,5, 6, or 7 carbon atoms. Thus, alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 1-methylcyclopropyl.
As used herein, the term "alkenyl" is meant to include 2 to 12, e.g., 2 to 7 carbon atoms or 3 to 7 carbon atoms. Alkenyl groups include at least one double bond. In some embodiments, alkenyl groups include vinyl, allyl, but-1-enyl, but-2-enyl, 2-dimethylvinyl, 2-dimethylprop-1-enyl, pent-2-enyl, 2, 3-dimethylbut-1-enyl, hex-2-enyl, hex-3-enyl, prop-1, 2-dienyl, 4-methylhex-1-enyl, prop-1-enyl, and the like.
As used herein, the term "alkoxy" relates to alkoxy groups containing from 1 to 12 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments, alkoxy groups contain 1 to 7 or 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. Thus, the term "alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 3-methylbutyloxy, 2-dimethylpropoxy, n-hexyloxy, 2-methylpentyloxy, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, n-heptyloxy, 2-methylhexyloxy, 2-dimethylpentyloxy, 2, 3-dimethylpentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and 1-methylcyclopropoxy.
As used herein, the term "aryl" is meant to include from 3 to 12 carbon atoms. Aryl may be phenyl or naphthyl. The above groups may be naturally substituted by any other known substituent in the field of organic chemistry. The group may also be substituted with two or more substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy and carbonyl. Halogen substituents may be bromo, fluoro, iodo and chloro. Alkyl groups are as defined above and contain 1 to 7 carbon atoms. Alkenyl groups are as defined above and contain 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms. Alkoxy groups are defined below and contain 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may contain unsaturated carbon atoms. Combinations of substituents may be present, for example trifluoromethyl.
As used herein, the term "heteroaryl" is meant to include any aryl group comprising 4 to 18 carbon atoms, wherein at least one atom of the ring is a heteroatom, i.e., not carbon. In some embodiments, the heteroaryl group can be a pyridine or indole group.
The above groups may be substituted with any other known substituent in the field of organic chemistry. The group may also be substituted with two or more substituents. Examples of substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy and carbonyl. Halogen substituents may be bromo, fluoro, iodo and chloro. Alkyl groups are as defined above and contain 1 to 7 carbon atoms. Alkenyl groups are as defined above and contain 2 to 7 carbon atoms, for example 2 to 4 carbon atoms. Alkoxy groups are defined below and contain 1 to 7 carbon atoms, for example 1 to 4 carbon atoms, which may contain unsaturated carbon atoms.
Mono-selenium-polyhydroxylated-cycloalkanes
In some embodiments, the compound is a monomeric selenium polyhydroxylated cycloalkane compound having formula (1) or formula (2):
wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, NH, CH2, Se, S, SO2, PO2, amino acids, heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein R is1、R2And R3Independently selected from CO, O2, SO2, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxy group, an alkenyl of at least 3 carbons substituted with a carboxy group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxy group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxy group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, a phenyl substituted with at least one dialkylamino group, a phenyl substituted with a phenyl group, Phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogenNaphthyl substituted by amino, naphthyl substituted by at least one alkylamino, naphthyl substituted by at least one dialkylamino, naphthyl substituted by at least one hydroxyl, naphthyl substituted by at least one carbonyl and naphthyl substituted by at least one substituted carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxyl, heteroaryl substituted by at least one halogen, heteroaryl substituted by at least one alkoxy, heteroaryl substituted by at least one nitro, heteroaryl substituted by at least one sulfo, heteroaryl substituted by at least one amino, heteroaryl substituted by at least one alkylamino, heteroaryl substituted by at least one dialkylamino, heteroaryl substituted by at least one hydroxyl, heteroaryl substituted by at least one carbonyl and heteroaryl substituted by at least one substituted carbonyl, and e) sugar, substituted sugar, D-galactose, substituted D-galactose, C3- [1,2,3]]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
Oligomeric selenium polyhydroxylated-cycloalkane compounds and dimeric selenium polyhydroxylated-cycloalkane compounds
In some embodiments, the compound is a di-polyhydroxylated-cycloalkane compound. In some embodiments, the compound is an oligomeric selenium polyhydroxylated-cycloalkane compound having 3 or more units.
In some embodiments, the compounds have the following general formulae (3) and (4) or a pharmaceutically acceptable salt or solvate thereof:
wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, SO2, PO2 and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein n is less than or equal to 24,
wherein R is1And R2Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxyl group, an alkenyl of at least 3 carbons substituted with a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxyl group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxyl group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxyl group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, or a pharmaceutically acceptable salt thereof, Heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, heteroaryl substituted by at least one amino group, heteroaryl substituted by at least one alkylamino group, heteroaryl substituted by at least one dialkylamino group, heteroaryl substituted by at least one hydroxyl groupHeteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) a saccharide, a substituted saccharide, D-galactose, a substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
In some embodiments, n ═ 1. In some embodiments, n ═ 2. In some embodiments, n ═ 3.
As used herein, the term "alkyl" refers to an alkyl group containing 1 to 7 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. The carbon atoms in the alkyl group may form a straight chain or a branched chain. The carbon atoms in the alkyl group may also form a ring containing 3, 4,5, 6 or 7 carbon atoms. Thus, the term "alkyl" as used herein includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 1-methylcyclopropyl.
In some embodiments, the compound is a 3-derivatized diseleno galactoside with fluorophenyl triazole.
Various aspects of the present invention relate to compounds of formula (7) or a pharmaceutically acceptable salt or solvate thereof:
in some embodiments, the compounds have the following general formulae (5) and (6) or a pharmaceutically acceptable salt or solvate thereof:
wherein X is Se, Se-S, S-Se, Se-SO2 or SO2-Se,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, P, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,
wherein R is1、R2、R3And R4Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxyl group, an alkenyl of at least 3 carbons substituted with a carboxyl group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxyl group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxyl group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxyl group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl groupAt least one carboxy-substituted heteroaryl group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one carbonyl group and a heteroaryl group substituted with at least one substituted carbonyl group, and e) a saccharide, a substituted saccharide, D-galactose, a substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
In some embodiments, halogen is a fluoro, chloro, bromo, or iodo group.
In some embodiments, the compound has the formula shown in table 1and is an inhibitor of galectin-3.
Non-limiting examples of monomeric Se galactosides are shown in Table 1.
TABLE 1
In some embodiments, the compound has the formula shown in table 2 and is an inhibitor of galectin-3.
Table 2 shows non-limiting examples of dise sugars.
TABLE 2
In some embodiments, the compound has the formula shown in table 3and is an inhibitor of galectin-3.
Table 3 shows non-limiting examples of oligomeric Se saccharides.
TABLE 3
The tetrameric Se-galactoside is expected to have a higher affinity for CRD than the trimeric structure due to the additional potential interaction of hydroxyl groups with amino acids in the vicinity of CRD (see example 14).
Without being bound by theory, the galactose-selenium compounds described herein have enhanced stability because their structures are less prone to hydrolysis (metabolism) and oxidation, e.g., aromatic rings without substituents, carbon-oxygen systems, carbon-nitrogen systems, and the like.
Calculated scoring of ligand-protein affinities
Standard assays for assessing the ability of a ligand to bind to a target molecule are known in the art and include, for example, ELISA, western blot and RIA. Suitable assays are described in detail herein. In some embodiments, binding kinetics (e.g., binding affinity) can be assessed by standard assays known in the art, such as by Biacore analysis. Assays to evaluate the effect of compounds on the functional properties of galectin are described in more detail herein.
One way to determine protein-ligand binding affinity uses a structure-based model that can predict the interaction of a protein-ligand complex that occurs when a ligand binds to a protein. Such structures can be studied by x-ray crystallography. In some embodiments, compounds of interest may be screened by "in silico" to predict the affinity of a ligand for a lectin or galectin protein using any scoring system known in the art.
In some embodiments, computational modeling may be used to facilitate structure-based drug design. Computer modeling models also enable visualization of and avoidance of protein-compound interactions, conformational strains, and possible spatial conflicts. In some embodiments, protein-ligand affinity may be scored using Glide (Schrodinger, Portland OR). The combination of the position and orientation of the ligand relative to the protein, along with flexible docking, is called the ligand pose and Glide scoring of the ligand pose is done by GlideScore. Glides Core is a quantitative measurement that provides an estimate of the free energy of ligand binding. It has many terms, including force field (electrostatic, van der waals forces, etc.) contributions and reward (reward) or penalty (penalty) terms for interactions known to affect ligand binding. It contains two energy elements; enthalpy and entropy contributions of the biological reactions. The thermodynamic principle of enthalpy-entropy compensation is based on the fact that: as the binding becomes stronger, the enthalpy becomes more negative, and the entropy tends to decrease as a result of the formation of tight complexes. Thus, the ligand with the lowest Glides core can be selected.
Methods and compounds for inhibiting galectin-3 and/or galectin-1 are provided, however the in silico models, assays, and compounds described herein may be applied to other galectin proteins and lectins.
A computer-simulated model of galectin-3 CRD was used, which was based on the 1KJR crystal structure of human galectin-3 CRD (Sorme, P., et al, (2005), "J.Am.chem.Soc.). 127: 1737-1743) and was improved using known" active "and" inactive "compounds of galectin-3 as training and test sets. The 1KJR crystal structure was chosen because of its unique extended cavity, allowing for a larger substituent at the C3 position of galactose (e.g. indole or naphthalene) (Vargas-Berebgurl 2013, Barondes 1998, Sorme 2003). Table 4 shows the GlideScore of the different digalactosides: (1) thiogalactoside, galactoside, selengalactoside, and diselenide with the same substituent.
TABLE 4
Glides core data show that the anomeric carbon for selenium incorporation into galactose (G-625) has the same score as thiogalactoside (TD-139, also known as G-240). The results also indicate that thiogalactoside (TD-139) and selenoglalactoside compounds (G-625) have a comparable overall estimated free energy predictor. Therefore, thiogalactoside (TD-139) and selenoglalactoside compounds (G-625) are expected to have affinity and inhibitory effect comparable to galectin-3.
The affinity of these compounds for integrin and galectin-3 was tested. Surprisingly, selenoglycoside compound (G-625) showed about at least 2-fold to about at least 3-fold better affinity for galectin-3and integrin.
The Se atom allows the rest of the molecule (e.g. G-625) to achieve the observed interaction with TD-139, but has a better affinity for TD-139 than galectin-3 as shown in Elisa-based assays and fluorescence polarization assays. In some embodiments, the seleno galactoside of formula (1) has at least two-fold or at least three-fold greater affinity for galectin-3 than TD-139. In some embodiments, a seleno galactoside of the invention has at least two-fold or at least three-fold greater affinity for galectin-3 than the corresponding thiogalactoside.
The 'druggability' characteristics defined by computational structural analysis take into account the compounds: (1) stereo-isomerization, (2) the position of the hydroxyl group on the sugar (e.g., axial or equatorial), and (3) the position and nature of the substituent.
1) And (3) stereo isomerization: it should be noted that compounds with the same 2D nomenclature may have different 3D structures, which may result in very different binding poses as well as different predicted binding free energy predictors, glidisescore.
2) Hydroxyl group: the position of the hydroxyl group on the sugar (e.g., axial or equatorial) plays an important role in compound binding. In particular, the present invention relates to galactose based compounds bound to the selenium atom bound to the anomeric carbon, which act as linking groups for the rest of the molecule.
3) Substituent(s): according to some aspects, the compounds may have substituents that are capable of or designed to reach amino acids that are part of binding sites that are known and unknown to play a role in ligand binding. One skilled in the art will appreciate that galectins bind the monosaccharide galactose with dissociation constants in the millimolar range. It has been shown that the addition of N-acetylglucosamine to galactose provides additional interaction with neighboring sites, enhancing the affinity of the compound for galectin-3 by more than 10-fold (Bachhawat-sikder et al, FEBS Lett.2001, 6.29 days; 500 (1-2): 75-9).
Further addition of non-natural derivatives, such as naphthol, at the3 position of the saccharide can increase the affinity to the low micromolar range, e.g. 0.003 mM. This substitution takes advantage of the cation-pi interaction with the surface residue Arg 144.
Human galectin-3 has shallow cavity and high solvent accessibility. It is very hydrophilic, but is able to form cation-pi interactions with Arg144 and possibly Trp181 (Magnani2009, Logan 2011). It has been shown that, upon ligand binding, Arg144 moves 3.5A upward from the protein surface to form a pocket for Arene-Arginine (Arene-Arginine) interactions. It should be noted that Arg144 is not present in other galectins (e.g., Gal-1, Gal-9) and this is being exploited in our in silico model. Similarly, potency can be improved by exploiting the cation-pi interaction with the surface residues of Arg 186. For example, triazole substitution at C3 of galactose has been reported to increase the affinity of galectin3 (Salamh BA et al, Bioorg. Med. chem. Lett., 7.15.2005; 15 (14): 3344-6).
Tryptophan 181 of subsite C is conserved throughout the galectin family. In all reported galectin-sugar complexes, there is a pi-pi stacking interaction between the Trp181(W181) side chain and the carbohydrate residue accommodated in subsite C (galactose is a natural sugar possessor).
In order to develop an effective approach to structure-based design approaches for highly potent galectin inhibitors (e.g., galectin-3 inhibitors), it is important to understand the detailed molecular basis of carbohydrate recognition based on the three-dimensional structure and physicochemical properties of conserved binding sequences. High Resolution structural information is of great help in this regard (see Ultra-High-Resolution Structures and Water Dynamics), Saraboji, K et al, Biochemistry, 2012, 1/10; 51 (1): 296-306). Although it is clear that the galectin-3 CRD site was pre-organized to recognize the sugar-like structure of oxygen (see fig. 2), it is not expected to recognize selenium-containing compounds with two to three times increased activity.
In galectin-3 (see figure 3 for the CRD amino acids in the vicinity of the binding pocket), the side chain of Arg144 can adopt different conformations due to its inherent flexibility, which may contribute to greater affinity by interacting with the arginine-arene of the aromatic moiety (cation-pi or pi-pi stacking).
In some embodiments, critical residues of galectin that affect ligand affinity are identified using computational Alanine Scanning Mutagenesis (ASM) or "in silico alanine scanning". ASM can be performed by sequential replacement of individual residues with alanine to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of a single amino acid to the function of the protein.
To better understand the importance of residues in the CRD binding pocket (fig. 3), "in silico alanine scanning" was performed by docking the compound of formula 1 with galectin-3 inhibitor, 3' -dideoxy-3, 3' -bis- [4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl ] -I, I ' -sulfanyldiyl-di-D-galactopyranoside (TD139, see W02016005311 a1, incorporated by reference in its entirety) in Glide. Residues predicted to be involved in binding were mutated, and it is expected that alanine mutations will have an effect on Glides core outcome. Alanine scanning was used to predict the importance of residues for ligand binding.
For example, galectin-3R 186S was reported to eliminate carbohydrate interactions. R186S has been shown to have selectively lost affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, and has lost the ability to activate neutrophils and intracellular targeting into vesicles. (see Salomonsson E. et al, J. Biochem., 11/5/2010; 285 (45): 35079-91).
Table 5 shows the results of comparison of in silico alanine scans using TD-139 compound
TABLE 5
Compound (I) | Substitution | GlideScore | dG |
TD-139 | Galectin-3 WT | -6.289 | 100.00 |
TD-139 | galectin-3-R186A | -5.345 | 84.99 |
TD-139 | galectin-3-R162A | -5.56 | 88.41 |
TD-139 | galectin-3-R144A | -6.502 | 103.39 |
TD-139 | galectin-3-W181A | -5.256 | 83.57 |
TD-139 | galectin-3-H158A | -5.315 | 84.51 |
TD-139 | galectin-3-N174A | -5.069 | 80.60 |
Table 6 shows the in silico alanine scan comparison using the G-625 compound having formula 1
TABLE 6
Compound (I) | Substitution | GlideScore | dG |
G-625 | Galectin-3 WT | -6.254 | 100 |
G-625 | galectin-3-R186A | -5.989 | 95.76 |
G-625 | galectin-3-R162A | -5.637 | 90.13 |
G-625 | galectin-3-R144A | -6.564 | 104.96 |
G-625 | galectin-3-W181A | -5.37 | 85.87 |
G-625 | galectin-3-H158A | -5.178 | 82.80 |
G-625 | galectin-3-N174A | -5.074 | 81.13 |
dG >100 indicates increased ligand binding upon alanine mutation, whereas dG <100 indicates decreased ligand binding upon mutation.
These results indicate that the "molecular interaction spectrum" of TD-139 is different from that of G-625. Tables 5 and 6 show the interaction spectra predicted by the computer simulation model. TD139 was greatly affected by the introduction of the R186A mutation (there was an "approximately 15% reduction" in glidisescor as a predictor of free binding energy). On the other hand, R186A had less effect on G625, which was more sensitive to the H158A mutation.
Surprisingly, alanine scanning showed that residue N174 plays an important role in the binding of TD-139 and G-625 compounds. Without being bound by theory, residue N174 may help to position the galactose core in an "optimal orientation" that will enable the CRD site to recognize the glycoid structure of the oxygen.
In silico alanine scanning showed that G-625 has unique binding properties while retaining interaction with known CRD residues such as Arg162, Arg 186 and Arg 144. Based on these results, site a was explored: s237, site B: d148, site C-D: interaction of a146, K176, G182 and E165 and N166 in the C loop of position (fig. 2 and 3) with CRD.
Synthetic route
The compounds of the present invention can be prepared by the following general methods and procedures. It is to be understood that typical or preferred process conditions (e.g., reaction temperature, time, molar ratios of reactants, solvents, pressure, pH, etc.) are given therein, and that other process conditions may be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants, solvents used, and pH, among other factors, but such conditions may be determined by one skilled in the art through routine optimization procedures.
In some embodiments, the compounds are synthesized using the synthetic route shown in figure 4.
For example, compound G-625 was prepared as detailed in example 10.
Pharmaceutical composition
Various aspects of the present invention relate to the use of a compound described herein for the preparation of a medicament. Some embodiments relate to a compound or use of a compound having formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments relate to a compound or use of a compound of tables 1-4.
Various aspects of the invention relate to pharmaceutical compositions comprising one or more compounds described herein. In some embodiments, the pharmaceutical composition comprises one or more of the following: pharmaceutically acceptable adjuvants, diluents, excipients and carriers.
The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a subject (e.g., patient) with a composition of the invention, does not destroy the pharmacological activity thereof, and is non-toxic when administered at a dose sufficient to provide a therapeutic or effective amount of the compound.
By "pharmaceutically acceptable carrier" is meant any and all solvents, dispersion media. The use of such media and compounds for pharmaceutically active substances is well known in the art. Preferably, the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the effects of acids and other natural conditions that inactivate the compound.
Some aspects of the invention relate to pharmaceutical compositions comprising a compound of the invention and optionally a pharmaceutically acceptable additive such as a carrier or excipient. In some embodiments, a pharmaceutical composition comprises a compound of formula (1), (2), (3), (4), (5), (6), or (7), or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable additive such as a carrier or excipient. In some embodiments, a pharmaceutical composition comprises a compound of tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.
In some embodiments, the pharmaceutical composition comprises a compound described herein as an active ingredient, in combination with a pharmaceutically acceptable adjuvant, diluent, excipient, or carrier. The pharmaceutical composition may comprise 1-99 wt% of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier and 1-99 wt% of a compound described herein.
Adjuvants, diluents, excipients and/or carriers that may be used in the compositions of the invention are pharmaceutically acceptable, i.e., compatible with the compounds and other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. Adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the invention are well known to those skilled in the art.
Effective oral dosages of the compounds of the present invention for experimental animals or humans may be formulated with various excipients and additives that enhance absorption of the compounds through the stomach and small intestine.
The pharmaceutical compositions of the invention may comprise two or more compounds of the invention. The compositions may also be used with other drugs used in the art for the treatment of the associated disorders.
In some embodiments, a pharmaceutical composition comprising one or more of the compounds described herein may be suitable for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract, e.g., in the form of an aerosol or air-suspended fine powder, or for administration via the eye, intraocular, intravitreal, or cornea.
In some embodiments, a pharmaceutical composition comprising one or more of the compounds described herein can be in the form of, for example, a tablet, a capsule, a powder, an injectable solution, a nebulized solution, an ointment, a transdermal patch, or a suppository.
Some aspects of the invention relate to pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.
The effective oral dose may be 10 times and up to 100 times the effective parenteral (partial) dose.
An effective oral dose may be administered in a once or divided dose per day, or twice, three times or monthly.
In some embodiments, a compound described herein may be co-administered with one or more other therapeutic agents. In certain embodiments, the additional agent may be administered separately from the compound of the invention as part of a multiple dose regimen (e.g., sequentially, e.g., on different overlapping schedules, with administration of the compound of the invention). In other embodiments, these agents may be part of a single dosage form, mixed in a single composition with the compounds of the present invention. In another embodiment, these agents may be administered as a single dose administered at about the same time as the compound of the present invention. When the composition includes a combination of a compound of the present invention and one or more additional therapeutic or prophylactic agents, the dosage level of both the compound and the additional agent can be between about 1% and 100%, and more preferably between about 5% and 95%, of the dosage normally administered in monotherapy.
In some embodiments, a therapeutically effective amount of a compound or composition may be compatible and effectively combined with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other drugs and nutraceuticals or supplements, or combinations thereof, but is not limited thereto.
In some embodiments, a compound of formula (1), (2), (3), (4), (5), (6), or (7) or a compound of tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, a compound of formula (1), (2), (3), (4), (5), (6), or (7) or a compound of tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, a compound of formula (1), (2), (3), (4), (5), (6), or (7) or a compound of tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, is administered with one or more antidiabetic agents. In some embodiments, administration of a compound of the invention and an active agent produces a synergistic effect. In some embodiments, the active agent is an anti-diabetic drug.
As used herein, the term "synergistic effect" refers to the correlated effects of two or more agents of the invention such that the combined effect is greater than the sum of the individual effects. In some embodiments, the compound of the invention and the active agent may be administered simultaneously or sequentially.
Various aspects of the invention relate to compositions or compounds for treating neoplastic disorders in combination with other antineoplastic agents, including but not limited to checkpoint inhibitors (anti-CTLA 2, anti-PD 1, anti-PDL 1 antibodies), other immunomodulators, including but not limited to anti-OX 40 and various other antineoplastic agents of various mechanisms.
Various aspects of the invention relate to compositions or compounds for treating neoplastic disorders in combination with other antineoplastic agents, including but not limited to checkpoint inhibitors (anti-CTLA 2, anti-PD 1, anti-PDL 1 antibodies), other immunomodulators, including but not limited to anti-OX 40 and various other antineoplastic agents of various mechanisms.
Method of treatment
Some aspects of the invention relate to the use of a compound described herein or a composition described herein for treating a disorder associated with the binding of galectins to ligands. In some embodiments, the galectin is galectin-3.
Some aspects of the invention relate to methods of treating various disorders associated with galectin binding to ligands. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound described herein. In some embodiments, the subject in need thereof is a human having high levels of galectin-3. The level of galectin, e.g., galectin-3, can be quantified using any method known in the art.
Some aspects of the invention relate to methods of treating diseases caused by disruption of TGFb1 (transforming growth factor β 1) activity by reversing galectin-3 interaction with its receptor (TGFb 1-receptor), thereby restoring normal regenerative activity in tissues.
Some aspects of the invention relate to methods of treating diseases associated with the transforming growth factor beta signaling pathway involving many cellular and pathological processes in adult and embryonic development, including cell growth, cell differentiation, apoptosis, cellular homeostasis, and other cellular functions.
Some aspects of the invention relate to a method for treating a disorder associated with galectin binding, e.g., galectin-3binding to insulin receptor or TGFb 1-receptor in a human, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of at least one compound of formula (1), (2), (3), (4), (5), (6) or (7) or tables 1-4, or a pharmaceutically acceptable salt or solvate thereof.
Various aspects of the invention relate to compounds, compositions, and methods for treating various disorders in which lectin proteins play a role in pathogenesis, including, but not limited to, the treatment of systemic insulin resistance. In some embodiments, the compounds reversibly bind to galectin-3 of the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
Various aspects of the present invention relate to compounds, compositions and methods for the treatment of (but not limited to) systemic insulin resistance. In some embodiments, systemic insulin resistance is associated with obesity, wherein elevated galectin-3 interacts with insulin receptors. In some embodiments, treatment with a compound of the invention can restore sensitivity to insulin activity in various tissues.
Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 1 diabetes. Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 2 diabetes (T2 DM). Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores sensitivity of the cell to insulin activity. In some embodiments, the compounds inhibit galectin-3 interaction with insulin receptors, which interferes with insulin binding and cellular glucose uptake mechanisms. Various aspects of the present invention relate to compounds, compositions and methods for treating low level inflammation resulting from insulin resistance in skeletal muscle and liver due to elevated levels of free fatty acids and triglycerides, leading to atherosclerotic vascular disease and NAFLD. Various aspects of the present invention relate to compounds, compositions and methods for treating polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance and compensatory hyperinsulinemia affecting approximately 65-70% of PCOS women. Various aspects of the present invention relate to compounds, compositions and methods for treating diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGF β receptor pathways in chronic disorders of the kidney. In some embodiments, the compounds can inhibit the overexpression of the TGF β receptor signaling system triggered by insulin resistance in diabetic patients and cause reduced renal function, and can reverse established lesions of diabetic glomerulopathy.
In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with one or more antidiabetic drugs. In some embodiments, administration of a compound of the invention and an active agent produces a synergistic effect.
Various aspects of the present invention relate to compounds, compositions, and methods for treating systemic insulin resistance associated with obesity, wherein elevated galectin-3 interacts with insulin receptors. In some embodiments, treatment with a compound of the invention can restore sensitivity to insulin activity in various tissues.
In some embodiments, the compounds or compositions of the present invention bind to the insulin receptor (also known as IR, INSR, CD220, HHF 5).
Various aspects of the invention relate to compounds, compositions and methods for treating disorders caused by disruption of TGFb1 (transforming growth factor β 1) activity.
In some embodiments, the disorder is an inflammatory disease, such as inflammatory bowel disease, crohn's disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
In some embodiments, the disorder is fibrosis, e.g., liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, or fibrosis of any organ that impairs normal function of the organ.
In some embodiments, the disorder is cancer.
In some embodiments, the disorder is an autoimmune disease, such as rheumatoid arthritis and multiple sclerosis.
In some embodiments, the disorder is heart disease or heart failure.
In some embodiments, the disorder is a metabolic disorder, such as diabetes.
In some embodiments, the associated disorder is pathological angiogenesis, e.g., ocular angiogenesis, a disease or disorder associated with ocular angiogenesis, and cancer.
In some embodiments, the compositions or compounds may be used to treat non-alcoholic steatohepatitis, inflammatory and autoimmune diseases, neoplastic disorders, or cancer with or without liver fibrosis.
In some embodiments, the composition may be used to treat liver fibrosis, kidney fibrosis, lung fibrosis, or cardiac fibrosis.
In some embodiments, the composition or compound is capable of enhancing anti-fibrotic activity in an organ (including but not limited to liver, kidney, lung, and heart).
In some embodiments, the compositions or compounds may be used to treat inflammatory diseases of the vasculature, including atherosclerosis and pulmonary hypertension.
In some embodiments, the compositions or compounds may be used to treat heart disease, including heart failure, cardiac arrhythmias, and uremic cardiomyopathy.
In some embodiments, the compositions or compounds may be used to treat kidney diseases, including glomerulopathy and interstitial nephritis.
In some embodiments, the compositions or compounds may be used to treat inflammatory, proliferative, and fibrotic skin diseases, including but not limited to psoriasis and scleroderma.
Various aspects of the invention relate to methods of treating allergic or atopic disorders, including but not limited to eczema, atopic dermatitis or asthma.
Various aspects of the invention relate to methods of treating inflammatory and fibrotic disorders in which galectins are at least partially implicated in pathogenesis by enhancing anti-fibrotic activity in organs including, but not limited to, the liver, kidney, lung and heart.
Various aspects of the present invention relate to compositions or compounds having therapeutic activity for the treatment of non-alcoholic steatohepatitis (NASH). In other aspects, the invention relates to methods of reducing the pathology and disease activity associated with non-alcoholic steatohepatitis (NASH).
Various aspects of the invention relate to compositions or compounds for treating inflammatory and autoimmune diseases or methods of treating inflammatory and autoimmune disorders in which galectins are involved, at least in part, in pathogenesis, including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
Various aspects of the present invention relate to compositions or compounds for treating neoplastic disorders (e.g., benign or malignant neoplastic diseases) in which galectins are at least partially involved in pathogenesis by inhibiting processes facilitated by galectin increase. In some embodiments, the invention relates to a method of treating a neoplastic disease (e.g., a benign or malignant neoplastic disease) in which a process facilitated by the inhibition of galectin increase is at least partially involved in pathogenesis. In some embodiments, the compositions or compounds can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the compositions or compounds may be used to treat primary and secondary cancers.
In some embodiments, the compound is a monomeric selenium polyhydroxylated cycloalkane compound, or a pharmaceutically acceptable salt or solvate thereof:
wherein X is selenium;
wherein Z is selected from the group consisting of O, S, C, NH, CH2, Se, R2And R3A carbohydrate or linker of (a);
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se;
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids, and combinations thereof.
Wherein R is1、R2And R3Independently selected from the group consisting of CO, SO2, SO, PO2, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons including heterocyclic substituents having a molecular weight of about 50-200D.
In some embodiments, the hydrophobic linear and cyclic hydrocarbons may include one of: a) an alkyl of at least 4 carbons, an alkenyl of at least 4 carbons, an alkyl of at least 4 carbons substituted by a carboxyl group, an alkenyl of at least 4 carbons substituted by a carboxyl group, an alkyl of at least 4 carbons substituted by an amino group, an alkenyl of at least 4 carbons substituted by an amino group, an alkyl of at least 4 carbons substituted by both an amino group and a carboxyl group, an alkenyl of at least 4 carbons substituted by both an amino group and a carboxyl group, and an alkyl substituted by one or more halogens, b) a phenyl substituted by at least one carboxyl group, a phenyl substituted by at least one halogen, a phenyl substituted by at least one alkoxy group, a phenyl substituted by at least one nitro group, a phenyl substituted by at least one sulfo group, a phenyl substituted by at least one amino group, a phenyl substituted by at least one alkylamino group, a phenyl substituted by at least one dialkylamino group, a phenyl substituted by at least one hydroxyl group, Phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, Heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino, substituted amino, imino, or substituted imino.
In some embodiments, the compound is a di-polyhydroxylated-cycloalkane compound.
In some embodiments, the compound has the general formula (xxxvi) or a pharmaceutically acceptable salt or solvate thereof:
wherein X is Se, Se-Se or Se-S;
wherein Z is independently selected from the group consisting of carbohydrates (including, for example, oligomeric Se-galactosides) or from O, S, C, NH, CH2, Se and R3And R4A linker consisting of the amino acid of (a);
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se;
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, and an amino acid;
wherein R is1、R2、R3And R4Independently selected from the group consisting of CO, SO2, SO, PO2, PO, CH, hydrogen, and hydrophobic linear and cyclic hydrocarbons, including heterocyclic substituents having a molecular weight of about 50-200D.
In some embodiments, the hydrophobic linear and cyclic hydrocarbons may include one of: a) an alkyl of at least 4 carbons, an alkenyl of at least 4 carbons, an alkyl of at least 4 carbons substituted by a carboxyl group, an alkenyl of at least 4 carbons substituted by a carboxyl group, an alkyl of at least 4 carbons substituted by an amino group, an alkenyl of at least 4 carbons substituted by an amino group, an alkyl of at least 4 carbons substituted by both an amino group and a carboxyl group, an alkenyl of at least 4 carbons substituted by both an amino group and a carboxyl group, and an alkyl substituted by one or more halogens, b) a phenyl substituted by at least one carboxyl group, a phenyl substituted by at least one halogen, a phenyl substituted by at least one alkoxy group, a phenyl substituted by at least one nitro group, a phenyl substituted by at least one sulfo group, a phenyl substituted by at least one amino group, a phenyl substituted by at least one alkylamino group, a phenyl substituted by at least one dialkylamino group, a phenyl substituted by at least one hydroxyl group, Phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, Heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino, substituted amino, imino, or substituted imino.
The present invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof:
wherein n is less than or equal to 24;
wherein X is Se, Se-Se or Se-S;
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se;
wherein Y and Z are independently selected from the group consisting of O, S, C, NH, CH2, Se, and an amino acid;
wherein R is1And R2Independently selected from the group consisting of: CO, SO2, SO, PO2, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons, including hetero hydrocarbons with molecular weights of 50-200DRing substituents, including but not limited to:
a) an alkyl of at least 4 carbons, an alkenyl of at least 4 carbons, an alkyl of at least 4 carbons substituted with a carboxyl group, an alkenyl of at least 4 carbons substituted with a carboxyl group, an alkyl of at least 4 carbons substituted with an amino group, an alkenyl of at least 4 carbons substituted with an amino group, an alkyl of at least 4 carbons substituted with both an amino group and a carboxyl group, an alkenyl of at least 4 carbons substituted with both an amino group and a carboxyl group, and an alkyl substituted with one or more halogens;
b) phenyl substituted by at least one carboxyl group, phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy group, phenyl substituted by at least one nitro group, phenyl substituted by at least one sulfo group, phenyl substituted by at least one amino group, phenyl substituted by at least one alkylamino group, phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group,
c) naphthyl, naphthyl substituted by at least one carboxy group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxy group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group; and
d) heteroaryl, heteroaryl substituted with at least one carboxyl group, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one alkoxy group, heteroaryl substituted with at least one nitro group, heteroaryl substituted with at least one sulfo group, heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group,
e) a sugar; a substituted sugar; d-galactose; substituted D-galactose; c3- [1,2,3] -triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino, substituted amino, imino, or substituted imino.
Examples
Example 1: compounds that inhibit the binding of galectins to labeled probes
Fluorescein-labeled probes that bind galectin 3and other galectin proteins have been developed and used to establish assays (fig. 5A and 5B) that use fluorescence polarization ((r))Et al, biochemistry (Anal Biochem.), 11.1.2004; 334(1): 36-47) measuring the binding affinity of the ligand to the galectin protein.
The compounds described herein tightly bind to galectin-3and other galectin proteins and replace the fluorescein-labeled probe, IC, with high affinity using the assay (FIG. 5A)50(concentration at which 50% inhibition occurs) is from about 5 η M to about 40. mu.M50Is about 5nM to about 20 nM. In some embodiments, the IC50Is about 5nM to about 100 nM. In some embodiments, the IC50Is about 10nM to about 100 nM. In some embodiments, the IC50Is about 50nM to about 5. mu.M. In some embodiments, the IC50Is about 0.5. mu.M to about 10. mu.M. In some embodiments, the IC50Is about 5. mu.M to about 40. mu.M.
The compounds claimed in the present invention were synthesized (see tables 1,2, 3and fig. 4) and tested for binding to CRD in a fluorescence polarization assay (fig. 5A) and showed inhibitory activity (fig. 7).
G-625-a beta-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl-) -beta-D-galactopyranosyl-3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) -1-seleno-. G-625 has a single selenidation bridge between two aryl-triazole-galactosides, (see table 2) has been shown to inhibit Gal-3 binding in fluorescence polarization assays (fig. 7).
G-626-a beta-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl-) -beta-D-galactopyranosyl-3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) -1-seleno-. G-625 has a diselenide bridge between two aryl-triazole-galactosides, (see table 2) has been shown to inhibit Gal-3 binding in fluorescence polarization assays (fig. 7).
G-662 (a seleno-monosaccharide) was synthesized (see Table 1) and shown to inhibit Gal-3 binding in a fluorescence polarization assay (FIG. 7).
Example 2: inhibition of galectin binding by compounds using FRET assay
A FRET (fluorescence resonance energy transfer) assay was developed for evaluating the interaction of galectin proteins (including but not limited to galectin-3) with model fluorescently labeled probes (see fig. 5B). The compounds described herein bind tightly to galectin-3and other galectin proteins using assays and displacing probes with high affinity having an IC of about 5nM to about 40 μ M using assays50(concentration at 50% inhibition). In some embodiments, IC50 is about 5nM to about 20 nM. In some embodiments, IC50 is about 5nM to about 100 nM. In some embodiments, IC50 is about 10nM to about 100 nM. In some embodiments, IC50 is about 50nM to about 5 μ M. In some embodiments, IC50 is about 0.5 μ Μ to about 10 μ Μ. In some embodiments, IC50 is about 5 μ Μ to about 40 μ Μ.
Example 3: compounds that inhibit the binding of galectins to physiological ligands
High levels of serum galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a persistent disease that can be resolved or carefully prevented. It is one of the most common metabolic syndromes around the world. Diabetes is primarily associated with the central and peripheral nervous systems and is a chronic complication. Diabetes is a common metabolic syndrome of diabetes, and the body cannot use glucose and stores it in the blood, possibly damaging the kidneys, nerves, heart, eyes and causing other complications.
Insulin resistance is a characteristic manifestation of patients with diabetic (T2DM) complications and is one of the clinical features of metabolic syndrome (MetS), a group of biochemical and metabolic diseases that are estimated to affect over 20% of adults (> 20 years) or approximately 5 billion americans in the united states. This figure may rise dramatically in the future since the prevalence of obesity shows no sign of reversion.
Insulin is a hormone that has multiple functions, including facilitating transport of nutrients into cells, regulating various enzymatic activities, and regulating energy homeostasis. These functions involve glucose metabolism in the liver, adipose tissue and muscle through intracellular signaling pathways. In the liver, insulin resistance leads to increased hepatic glucose production. In adipose tissue, insulin resistance affects lipase activity, resulting in antilipidemic effects, affecting free fatty acid flow out of adipocytes, increasing circulating free fatty acids.
Recent studies have also shown that galectin-3 plasma levels are significantly elevated in human and animal obesity models.
It has been reported that in obesity, macrophages and other immune cells are recruited to insulin target tissues and contribute to chronic inflammatory states and insulin resistance. Galectin-3, which is known to be secreted mainly by macrophages, may play a key role in this inflammatory process, and thus it links inflammation to a decrease in insulin sensitivity. Inhibition of galectin-3 may be a new drug target for the treatment of insulin resistance.
The interaction of the insulin receptor and insulin is the checkpoint for the second pathway, Ras-mitogen-activated protein kinase (MAPK), which mediates gene expression, and also influences the PI3K-AKT pathway that controls cell growth and differentiation. Insulin Receptor Substrates (IRS) are common intermediates, including four different family members IRS 1-4. Defects in insulin signaling often involve insulin receptor substrate-1 (IRS 1). Activation of the insulin receptor increases tyrosine phosphorylation of IRS1, thereby initiating signal transduction. However, when serine 307 is phosphorylated, signaling is reduced. Other negative regulators associated with inflammation of IR or IRs1, including cytokine signaling inhibitors (Socs), may promote ubiquitination, in which ubiquitin (a small protein) binds to another target protein, alters its function and subsequently degrades, e.g., IRs inactivation.
The presently claimed compounds were synthesized (see tables 1,2, 3and 4) and tested for inhibitory activity in the insulin receptor-galectin-3 interaction (fig. 6B).
For example, G-625-a beta-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl-) -beta-D-galactopyranosyl-3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) -1-seleno-. G-625 has a single selenidation bridge between two aryl-triazole-galactosides (see table 2), which shows inhibitory activity in the insulin receptor-galectin-3 interaction (fig. 8).
G-662 (a seleno-monosaccharide) was synthesized (see table 1) and showed inhibitory activity in the insulin receptor-galectin-3 interaction (fig. 8).
The claimed compounds of the present invention were synthesized (see tables 1,2, 3and 4) and tested for their inhibitory activity against TGF- β -1 receptor-galectin-3 interaction. This interaction of TGF-beta receptors with galectin-3 is an important pathological step in many inflammatory and fibrotic pathways. It has been shown that the compounds described herein are inhibitors of this interaction (figure 9).
For example, G-625-a beta-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl-) -beta-D-galactopyranosyl-3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) -1-seleno-. G-625 has a single selenidation bridge between two aryl-triazole-galactosides (see table 2), which shows inhibitory activity in TGF- β receptor-galectin-3 (figure 9).
G-662 (a seleno-monosaccharide) was synthesized (see table 1), showing inhibitory activity in TGF- β receptor-galectin-3 interaction (figure 9).
Example 4: compounds that bind to amino acid residues in galectin proteins
Heteronuclear NMR spectroscopy was used to evaluate the interaction of the compounds described herein with galectin molecules, including but not limited to galectin-3, to evaluate interacting residues on the galectin-3 molecule.
Expression was uniform in BL21(DE3) competent cells (Novagen)15N-labeled Gal-3, grown in minimal medium, purified on a lactose affinity column and fractionated on a gel filtration column as previously described for the 1H,13C and 15N backbone and side chain chemical shift assignments (1H,13C, and 15N backbone and side-chain chemical shift assignments for the 29kDa human galectin-1protein dimer) of Gal-1(Nesmelova IV, Pang M, Baum LG, Mayo KH, 29kDa human galectin-1protein dimer), "biomolecule nuclear magnetic resonance assignments (Biomol NMR assignment), 2008. 12 months; 2(2): 203-.
Using 95% H2O/5%D2O mixture dissolved in 20mM potassium phosphate buffer pH 7.0 at a concentration of 2mg/ml15N-labeled Gal-3. By using1H-15N HSQC NMR experiments to study binding of a series of compounds described herein. Previously reported for recombinant human Gal-31H and15n resonance assignments (Ipepel H et al, (1) H, (13) C, and (15) N backbone and side chain chemical shift assignments for 36proline-containing, full-length 29kDa human chimeric galectin-3 ((1) H, (13) C, and (15) N backbone and side-chain chemical shift assignments for the36 proline-linking, full length H29 kDa human chimera a-type lectin-3), "biomolecule nuclear magnetic resonance assignments" (biomolecular NMR assignment, 4 months of 2015; 9): 59-63).
NMR experiments were performed on a Bruker 600MHz, 700MHz or 850MHz spectrometer equipped with an H/C/N triple resonance probe and an x/y/z triaxial pulsed field gradient unit at 30 ℃. Using two dimensions1H-15N HSQC gradient sensitivity enhancement, applied to 256(t1) × 2048(t2) complex data points of nitrogen and proton dimensions, respectively, raw data were transformed and processed with NMRPipe and partitioned with NMRviewAnd (6) analyzing.
These experiments show the differences in binding residues of the carbohydrate binding domain of galectin-3 of the compounds described herein.
Example 5: cellular activity of cytokine activity associated with galectin binding inhibition
Example 1 describes the ability of the compounds of the present application to inhibit the binding of physiological ligands to galectin molecules. In the experiments of this example, the functional significance of those binding interactions was evaluated.
One of the interactions with galectin-3 that is inhibited by the compounds described herein is the TGF-beta receptor. Thus, experiments were performed to evaluate the effect of compounds on TGR- β receptor activity in cell lines. Various TGF- β responsive cell lines, including but not limited to LX-2 and THP-1 cells, are treated with TGF- β and cellular responses are measured by observing activation of the second messenger system, including but not limited to phosphorylation of various intracellular SMAD proteins. After determining that TGF- β activates the second messenger system in various cell lines, the cells were treated with the compounds described herein. These experiments show that these compounds inhibit the TGF- β signaling pathway, confirming that the binding interaction inhibition described in example 1 has a physiological role in cell models.
Cellular assays were also performed to assess the physiological significance of inhibiting galectin-3 interaction with various integrin molecules. Cell-cell interaction studies were performed using monocytes that bind to vascular endothelial cells as well as other cell lines. Treatment of cells with the compounds described herein was found to inhibit these integrin-dependent interactions, confirming that the binding interaction inhibition described in example 1 has a physiological role in cell models. The bioassay process comprises the following steps:
the process of MCF-7 cells (colon cancer) is as follows:
1. MCF-7 cells were suspended in medium containing 4-fold concentrate of penicillin/streptomycin (4X Pen/Strep) and 0.25% fetal bovine serum (Gibco batch 1202161).
2. 100ul of medium was added, about 4,000 and 10,000 cells/well, passage 5 to 30), and the cells were incubated at 37 ℃ for at least 24 hours.
3. Test compounds are serially diluted in assay medium as described above, typically in the range of 100. mu.g/ml to 20ng/ml
4. 100ml of serially diluted compound were added in duplicate to the cells in the assay plates, with a final volume of 200ml for each well (containing penicillin/streptomycin 2-fold concentrate (2x Pen/Strep), 0.25% FBS and the indicated compound)
5. Cells were incubated at 37 ℃ for 60-80 hours.
6. To each well was added 20ml of Promega substrate [ CellTiter96Aqueous single Solution (CellTiter96Aqueous One Solution) ] reagent.
7. Cells were incubated at 37 ℃ for 4-8 hours and OD read at 490 nm.
The process of HTB-38 cells (breast cancer) is as follows:
1. HTB-38 cells were resuspended in a medium containing 8ng/ml h-IFN-. gamma.penicillin/streptomycin 4-fold concentrate (4XPen/Strep) and 10% fetal bovine serum (Gibco batch 1260930).
2. Cells were transferred to assay plates at 100. mu.l/well (4,000-10,000 cells/well, passage 4-30).
3. Test compounds are serially diluted in assay medium as described above, typically in the range of 100. mu.g/ml to 20ng/ml
4. 100 μ l/well serial dilutions of compounds were added to cells in duplicate. The final volume of each well was 200. mu.l, containing 4ng/ml h-IFN-. gamma.penicillin/streptomycin 2-fold concentrate (2X Pen/Strep),
5. cells were incubated at 37 ℃ for 60-90 hours.
6. Mu.l Promega substrate [ CellTiter96Aqueous single Solution (CellTiter96Aqueous One Solution) ] reagent was added to each well.
7. Cells were incubated at 37 ℃ for 4-8 hours and OD read at 490 nm.
Cell motility assays were performed to assess the physiological significance of inhibiting galectin-3 interaction with the various integrins and other cell surface molecules defined in example 1. Cell studies were performed using a variety of cell lines in a semi-permeable membrane separation well device. Treatment of cells with the compounds described herein was found to inhibit cell motility, confirming that the inhibition of binding interactions described in example 1 has a physiological effect in a cellular model.
Example 6: in vitro inflammatory model (monocyte-based assay)
A macrophage polarization model was established starting from THP-1 monocyte cultures, which were differentiated into inflammatory macrophages using PMA (12-myristate 13-acetate Phorbol, Phorbol 12-myrsite 13-acetate) for 2-4 days. Once differentiated (MO macrophages), macrophages are induced with LPS or LPS and IFN- γ to activate macrophages (M1) into the inflammatory phase for 1-3 days. Cytokine and chemokine alignments were analyzed to confirm the polarization of THP-1 derived macrophages to the inflammatory stage. The effect of the anti-galectin 3 compound on macrophage polarization was first assessed by monitoring cell viability using a colorimetric method (using tetrazolium reagent) to determine the number of surviving cells in a proliferation or cytotoxicity assay (Promega, CeilTiter)An AQueous single solution cell proliferation assay comprising a novel tetrazolium compound [3- (4, 5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole, inner salt; MTS]And an electron coupling agent (phenazine ethosulfate; PES)) and the inflammatory stage was assessed by quantitative measurement of the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2), MCP-1/CCL2 being a key protein that regulates monocyte/macrophage migration and infiltration during inflammatory cells. The major active compounds were subjected to follow-up tests for expression and secretion of other cytokines and chemokines.
THP-1 cells are stimulated by microbial endotoxins and converted into inflammatory macrophages (M1), which secrete inflammatory cytokines such as monocyte chemotactic protein-1 (MCP-1).
In this example, the method steps are as follows:
1) culturing THP-1 cells in medium containing gentamicin
2) THP-1 cells were transferred to wells of a 96-well plate at 2,000 cells/well and incubated for 2 days in assay medium containing 10ng/ml PMA
3) Test compounds were serially diluted in LPS (10ng/ml) containing medium
4) 100ml of compound/LPS solution was added to each well to a final assay volume of 200ml for each well, each well also containing gentamicin and 5ng/ml PMA
5) Cells were incubated for up to 8 days.
6) Every other day 60ul of samples were taken for bioassay
7) At the end of this time, 15ml of a single solution of Promega substrate CeIlTiter 96Aqueous was added to each well to monitor cytotoxicity (at 490 nm)
8) For cell biomarker evaluation, cells were washed with 1 × PBS and extracted with 200 μ l lysis buffer for 1 hour. The extract spanned downward for 10 minutes and 120ul of sample was taken from the top. All samples were kept at-70 ℃ until testing.
Example 7: evaluation of Compound absorption, distribution, metabolism and Elimination
Physicochemical properties of the compounds described herein were evaluated, including but not limited to solubility (thermodynamic and kinetic methods), various pH changes, solubility in biologically relevant media (FaSSIF, FaSSGF, FeSSIF), Log D (octanol/water and cyclohexane/water), chemical stability in plasma, and blood partitioning.
Compounds described herein were evaluated for in vitro permeation properties including, but not limited to, PAMPA (parallel artificial membrane permeametry), Caco-2, and MDCK (wild-type).
Animal pharmacokinetic properties of the compounds described herein were evaluated, including but not limited to pharmacokinetics, tissue distribution, cerebral plasma ratio, bile excretion and mass balance, by various routes, i.e., oral, intravenous, intraperitoneal, subcutaneous administration in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (new zealand white rabbit), dogs (beagle), cynomolgus monkeys, etc.
Compounds described herein were evaluated for protein binding including, but not limited to, plasma protein binding (ultrafiltration and equilibrium dialysis) and microsomal protein binding.
The compounds described herein are evaluated for in vitro metabolism including, but not limited to, cytochrome P450 inhibition, cytochrome P450 time-dependent inhibition, metabolic stability, liver microsomal metabolism, S-9 component metabolism, effects on cryopreserved hepatocytes, plasma stability, and GSH capture.
Evaluation of compounds described herein for metabolite identification, including but not limited to in vitro identification (microsomes, S9 and hepatocytes) and in vivo samples.
Example 8: affinity of oligo-Se-galactosides
The affinities of the tetrameric and trimeric Se-galactosides of table 3 were determined using fluorescence polarization assay. The tetrameric Se-galactoside is expected to have a higher affinity for CRD than the trimeric structure due to the additional potential interaction of hydroxyl groups with amino acids in the vicinity of CRD.
Example 9: cell culture adipocyte model
Cell culture and insulin resistance models 3T3-L1 fibroblasts, 3T3-L1 fibroblasts were cultured in DMEM containing 10% FCS and GlutaMAX and differentiated into adipocytes as previously reported (Shewan, A.M., van Dam, E.M., Martin, S., Lun, T.B., Hong, W.J., and James, D.E. (2003), "GLUT 4 circulates across The Golgi Network (TGN) subdomain rich in Syntaxins 6and 16but not in TGN 38" ("GLUT 4 receptors a a a trans-Golgi word (TGN) subdomain of acidic targeting motifs," (TGN) subunit in Syntaxins 6and 16, and TGN38: biological cells of biological origin 9714. cell 9814, cell culture and cell 3. Biotic cell 973. biological cells. Various insulin resistance models were used. 3T3-L1 adipocytes were cultured in whole DMEM medium with different doses of insulin (10-100nM) to cause chronic insulin exposure, or with 0.1-1M Dexamethasone (DEX) at 37 ℃ for 8-24 hours or with 1-20ng/ml TNF at 37 ℃ for 48 h. The medium was replaced twice daily with fresh medium containing TNF. Following insulin resistance treatment, cells were washed, serum starved for 1-2 hours, then subjected to insulin stimulation and evaluated for insulin-regulated kinases and processes. This protocol has previously been shown to be sufficient to restore cells to their baseline level of GLUT4 translocation (Hoehn, k.l., Hohnen-Behrens, c., Cederberg, a., Wu, l.e., Turner, n., Yuasa, t., Ebina, y., and James, D.E. (2008) IRS1 independent defects define the major node of insulin resistance., (Cell metasb., 7,421-
Experiments were performed with 3T3-L1 fibroblasts differentiated into adipocyte cultures according to the Promega protocol:
1. on day 1, 1ml of low passage 3T3L1 cells were thawed and mixed with 9ml of Maintenance Medium (MM). Cells were centrifuged at 200Xg for 10 minutes and the liquid medium was aspirated.
2. The cell pellet was resuspended in 11ml MM. Cells were plated at 20,000 cells/100 μ l in 96-well plates.
3. Cells were incubated at 37 ℃ in 5% CO2Medium was grown to confluence and medium was changed every 2 days. Since these cells are less adherent during differentiation, the cells were plated on collagen-coated plates (Corning, catalog No. 356650). Media removal and addition was performed at the slowest pipetting speed possible.
4. On day 5, medium was replaced with 100 μ l of differentiation medium I (DM-I), and replacement continued every 2 days.
5. On day 12, the medium was replaced with 100. mu.l of differentiation medium II (DM-II).
6. On day 14, medium was replaced with 100. mu.l of MM, and medium replacement was continued every 2 days.
7. Insulin response was measured between 8-11 days.
3T3L1 adipocytes were determined as follows:
1. the day before the assay medium was replaced with 100 μ l of MM without serum.
2. On the day of the assay, a range of insulin concentrations were contained using 100 μ l of serum-or glucose-free DMEM (Life Technologies, Cat. No. f 11966). Cells were incubated at 37 ℃ in 5% CO2And incubated for 1 hour.
3. The medium was removed, 50. mu.l of 2DG (1mM) in PBS was added and the cells were incubated for 10 minutes at 25 ℃.
4. Add 25. mu.l stop buffer and shake the sample briefly.
5. Add 25. mu.l of neutralization buffer and briefly shake the sample.
6. Add 100. mu.l 2DG6P detection reagent, shake the sample briefly and incubate at 25 ℃ for 1 hour.
Luminescence was recorded at 0.3-1 second integration on a luminometer to assess the cellular effect of galectin-3 on glucose uptake.
Adipocyte differentiation is monitored by a variety of well-defined insulin-associated activation markers, including expression of Insulin Receptor (IR) and its activation by insulin, but not limited to IR kinase activity within minutes of exposure to insulin. This insulin activation was inhibited by treatment with galectin-3. The effect of galectin-3 on IR was also monitored by glucose uptake rate.
The compounds described herein were found to inhibit galectin-3 action and reversal of insulin resistance and restoration of glucose uptake, confirming the physiological and potential therapeutic effects in systemic insulin resistance in diabetes associated with obesity.
Example 10: synthesis of G-625
The G-625 compound was synthesized using the following scheme (see FIG. 4)
Step-1:
(2R,3R,4S,5R,6S) -2- (acetoxymethyl) -4-azido-6- ((4-methylbenzoyl) selenoalkyl) tetrahydro-2H-pyran-3, 5-diyl diacetate (3): to a solution of (2R,3R,4S,5R,6R) -2- (acetoxymethyl) -4-azido-6-bromotetrahydro-2H-pyran-3, 5-diyl diacetate (1, 1.6g, 4.06mmol) and potassium 4-methylbenzoate (2, 2.41g, 10.14mmol) in EtOAc (30mL) at room temperature (rt) was added tetra-n-butylammonium hydrogensulfate (2.75g, 8.12mmol) and Na sequentially2CO3Aqueous solution (16mL, 16mmol) and the reaction mixture was stirred at room temperature for 3hOrganic layer dried (Na)2SO4) Filtered and concentrated in vacuo, and the residue purified by flash column chromatography [ normal phase, silica gel (100-200 mesh, gradient 0-30% EtOAc in hexane)]) Purification gave the title compound (3) as a white solid (1.38g, 66%).
1H-NMR(400MHz;CDCI3):2.04(s,3H),2.06(s,3H),2.18(s,3H),2.45(s,3H),2.76-2.80(m,1H),4.03-4.17(m,3H),5.44-5.53(m,3H),7.27(d,J=8.1Hz,2H),7.75(d,J=8.1Hz,2H)。
Step-2:
(2S,2' S,3R,3' R,4S,4' S,5R,5' R,6R,6' R) -Selenobis (6- (acetoxymethyl) -4-azidotetrahydro-2H-pyran-2, 3, 5-triyl) tetraacetate (5): a solution of (2R,3R,4S,5R,6S) -2- (acetoxymethyl) -4-azido-6- ((4-methylbenzoyl) selenoalkyl) tetrahydro-2H-pyran-3, 5-diyl diacetate (3, 100mg, 0.19mmol) in DMF (4mL) was degassed with argon for 20 min. Cooling the mixture to-15 ℃ and Cs2CO3(127mg, 0.79mmol), dimethylamine (2M in THF) (0.39mL, 0.78mmol) and a solution of (2R,3R,4S,5R) -2- (acetoxymethyl) -4-azido-6-bromotetrahydro-2H-pyran-3, 5-diyl diacetate (307mg, 0.78mmol) in DMF (2mL) was added and degassed again with argon for 20 min. the reaction mixture was stirred at the same temperature for 5 min. after checking TLC, the reaction mixture was quenched with water (10mL) and extracted with EtOAc (3 × 15 mL). the combined organic layers were washed with brine and dried (Na, 2M)2SO4) Filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [ normal phase, silica gel (100-200 mesh, gradient 0-50% EtOAc in hexane)]) Purification gave the title compound (5) as a colorless viscous solid (66mg, 48%).
MS:m/z 707(M+AcOH)+(ES+)
1H-NMR (crude) (400 MHz; CDCl)3):2.04-2.19(m,18H),2.87-2.98(m,2H),4.09-4.17(m,6H),4.60-4.82(m,6H)。
Step-3:
(2S,2'S,3R,3' R,4S,4'S,5R,5' R,6R,6'R) -Selenobis (6- (acetoxymethyl) -4- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) tetrahydro-2H-pyran-2, 3, 5-triyl) tetraacetate (7) to a solution of (2S,2' S,3R,3'R,4S,4' S,5R,5'R,6R,6' R) -Selenobis (6- (acetoxymethyl) -4-azidotetrahydro-2H-pyran-2, 3, 5-triyl) tetraacetate (5, 130mg, 0.183mmol) and 1-ethynyl-3-fluorobenzene (6, 115mg, 0.918mmol) in toluene (4mL) was added DIPEA (0.07mL, 0.366mmol) and Cul (34mg, 0.183mmol) at room temperature and the reaction mixture was filtered, the reaction mixture was washed with water, filtered, and the reaction mixture was quenched with sodium alginate (16H), dried, filtered, and the reaction mixture was washed with water (20mL, 15H, dried, filtered, and the reaction mixture was washed with sodium alginate, filtered2SO4) And concentrated in vacuo, and the residue was washed with Et2O (10mL) to give the title compound (7) as a white solid (164mg, 94%).
MS:m/z 949(M+H)+(ES+)
1H-NMR(400MHz;DMSO-d6):1.83(s,3H),1.85(s,3H),1.90-2.07(m,12H),4.07-4.13(m,4H),4.32-4.40(m,2H),5.36(d,J=9.5Hz,1H),5.48-5.49(m,3H),5.64-5.73(m,4H),7.18(t,J=8.4Hz,2H),7.47-7.51(m,2H),7.68-7.74(m,4H),8.76(d,J=10.3Hz,2H)。
Step-4:
(2R,2'R, 3' R,4S,4'S,5R,5' R,6S,6'S) -6,6' -selenobis (4- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) -2- (hydroxymethyl) tetrahydro-2H-pyran-3, 5-diol) (GTJC-010-01): to a solution of (2S,2' S,3R,3' R,4S,4' S,5R,5' R,6R,6' R) -seleno-bis (6- (acetoxymethyl) -4- (4- (3-fluorophenyl) -1H-1,2, 3-triazol-1-yl) tetrahydro-2H-pyran-2, 3, 5-triyl) tetraacetate (7,200mg, 0.21mmol) in MeOH (10mL) was added NaOMe (0.4mL, 0.42mmol) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours. Upon completion, the reaction mixture was acidified with Amberlyst 15H (pH about 6), filtered, washed with MeOH and concentrated in vacuo. The crude residue was subjected to preparative HPLC (reverse phase, X BRIDGE Shield RP, C-18, 19X 250Mm, 5 μ, 50% -82% gradient of ACN in 5mM ammonium bicarbonate in water, 214nm, RT: 7.8min to give the title compound as a white solid (GTJC-010-01, 18 mg).
LCMS (method a): m/z 697(M + H)+(ES+) At 4.51min, the purity is 96%.
1H-NMR(400MHz;DMSO-d6):3.49-3.61(m,4H),3.72(t,J=6.2Hz,2H),3.99(dd,2.9&6.6Hz,2H),4.36-4.43(m,2H),4.70(t,J=5.5Hz,1H),4.82(dd,2.8&10.5Hz,2H),5.19(d,J=9.7Hz,2H),5.31(d,J=7.2Hz,2H),5.40(d,J=6.6Hz,2H),7.12-7.17(m,2H),7.46-7.51(m,2H),7.66(dd,J=2.3&10.2Hz,2H),7.72(d,J=7.8Hz,2H),8.67(s,2H)。
CMS (method a): the instrument comprises the following steps: waters Acquity UPLC, Waters 3100PDA detector, SQD; column: acquity BEH C-18, 1.7 microns, 2.1X 100 mm; gradient [ time (min)/solvent B (%) in a ]: 0.00/2, 2.00/2, 7.00/50, 8.50/80, 9.50/2, 10.0/2; solvent: solvent a ═ 5mM aqueous ammonium acetate; solvent B ═ acetonitrile; sample size 1 LL; the detection wavelength is 214 nm; the column temperature is 30 ℃; the flow rate was 0.3 mL/min.
All publications and patents mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. See international application No. PCT/US17/20658, filed 3/2017, which is incorporated by reference in its entirety.
Claims (29)
1. A method for treating systemic insulin resistance, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, NH, CH2, Se, S, SO2, PO2, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms,
wherein R is1、R2And R3Independently selected from CO, O2, SO2, PO2, PO, CH, hydrogen, or combinations of these, and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxy group, an alkenyl of at least 3 carbons substituted with a carboxy group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxy group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxy group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, a phenyl substituted with at least one dialkylamino group, a phenyl substituted with a phenyl group, Phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group, and the likeAt least one carboxy-substituted heteroaryl group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one carbonyl group and a heteroaryl group substituted with at least one substituted carbonyl group, and e) a saccharide, a substituted saccharide, D-galactose, a substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
2. A method for treating systemic insulin resistance, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (2) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, SO3, PO2, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms,
wherein R is1、R2And R3Independently selected from CO, O2, SO2, PO2, PO, CH, hydrogen or combinations of these, and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxyl group, an alkenyl group of at least 3 carbons substituted with a carboxyl group, an alkyl group of at least 3 carbons substituted with an amino group, an amino groupSubstituted alkenyl of at least 3 carbons, alkyl of at least 3 carbons substituted by both amino and carboxyl, alkenyl of at least 3 carbons substituted by both amino and carboxyl, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxyl, phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy, phenyl substituted by at least one nitro, phenyl substituted by at least one sulfo, phenyl substituted by at least one amino, phenyl substituted by at least one alkylamino, phenyl substituted by at least one dialkylamino, phenyl substituted by at least one hydroxyl, phenyl substituted by at least one carbonyl, and phenyl substituted by at least one substituted carbonyl, c) naphthyl, naphthyl substituted by at least one carboxyl, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, Naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, heteroaryl substituted by at least one amino group, heteroaryl substituted by at least one alkylamino group, heteroaryl substituted by at least one dialkylamino group, heteroaryl substituted by at least one hydroxyl group, heteroaryl substituted by at least one carbonyl group and heteroaryl substituted by at least one substituted carbonyl group, and e) a sugar; a substituted sugar; d-galactose; substituted D-galactose; c3- [1,2,3]Triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkenyl, aryl, heteroaryl and heterocycles and derivatives; amino, substituted amino, imino, and substituted imino.
3. A method for treating systemic insulin resistance, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (3) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbon derivatives comprising a heterocyclic substituent of 3 or more atoms,
wherein n is less than or equal to 24,
wherein R is1And R2Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen or combinations of these and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxy group, an alkenyl of at least 3 carbons substituted with a carboxy group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxy group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxy group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one nitro groupNaphthyl substituted by amino, naphthyl substituted by at least one alkylamino, naphthyl substituted by at least one dialkylamino, naphthyl substituted by at least one hydroxyl, naphthyl substituted by at least one carbonyl and naphthyl substituted by at least one substituted carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxyl, heteroaryl substituted by at least one halogen, heteroaryl substituted by at least one alkoxy, heteroaryl substituted by at least one nitro, heteroaryl substituted by at least one sulfo, heteroaryl substituted by at least one amino, heteroaryl substituted by at least one alkylamino, heteroaryl substituted by at least one dialkylamino, heteroaryl substituted by at least one hydroxyl, heteroaryl substituted by at least one carbonyl and heteroaryl substituted by at least one substituted carbonyl, and e) sugar, substituted sugar, D-galactose, substituted D-galactose, C3- [1,2,3]]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino or substituted imino.
4. A method for treating systemic insulin resistance, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (4) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is a group of elements selected from the group consisting of selenium,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbon derivatives comprising a heterocyclic substituent of 3 or more atoms,
wherein n is less than or equal to 24,
wherein R is1And R2Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen or combinations of these and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxy group, an alkenyl of at least 3 carbons substituted with a carboxy group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxy group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxy group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, or a pharmaceutically acceptable salt thereof, Heteroaryl substituted with at least one nitro group, heteroaryl substituted with at least one sulfo group, heteroaryl substituted with at least one amino group, heteroaryl substituted with at least one alkylamino group, heteroaryl substituted with at least one dialkylamino group, heteroaryl substituted with at least one hydroxyl group, heteroaryl substituted with at least one carbonyl group and heteroaryl substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen,Alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino, and substituted imino.
5. The method of claim 3, wherein n-1.
6. The method of claim 3, wherein n-3.
7. The method of claim 4, wherein n-1.
8. The method of claim 4, wherein n-3.
9. A method for treating systemic insulin resistance, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (5) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is Se, Se-S, S-Se, Se-SO2 or SO2-Se,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200D, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms,
wherein R is1、R2、R3And R4Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen or combinations of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxyl group, an alkenyl group of at least 3 carbons substituted with a carboxyl group, an alkyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with ammoniaAlkenyl of at least 3 carbons substituted by a group, alkyl of at least 3 carbons substituted by both amino and carboxyl, alkenyl of at least 3 carbons substituted by both amino and carboxyl, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxyl, phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy, phenyl substituted by at least one nitro, phenyl substituted by at least one sulfo, phenyl substituted by at least one amino, phenyl substituted by at least one alkylamino, phenyl substituted by at least one dialkylamino, phenyl substituted by at least one hydroxyl, phenyl substituted by at least one carbonyl, and phenyl substituted by at least one substituted carbonyl, c) naphthyl, naphthyl substituted by at least one carboxyl, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one dialkylamino group, naphthyl substituted by at least one hydroxyl group, naphthyl substituted by at least one carbonyl group and naphthyl substituted by at least one substituted carbonyl group, d) heteroaryl, heteroaryl substituted by at least one carboxyl group, heteroaryl substituted by at least one halogen group, heteroaryl substituted by at least one alkoxy group, heteroaryl substituted by at least one nitro group, heteroaryl substituted by at least one sulfo group, heteroaryl substituted by at least one amino group, heteroaryl substituted by at least one alkylamino group, heteroaryl substituted by at least one dialkylamino group, heteroaryl substituted by at least one hydroxyl group, heteroaryl substituted by at least one carbonyl group and heteroaryl substituted by at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycles and derivatives, amino, substituted amino, imino and substituted imino.
10. A method for treating systemic insulin resistance, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (6) or a pharmaceutically acceptable salt or solvate thereof
Wherein X is Se, Se-S, S-Se, Se-SO2 or SO2-Se,
wherein W is selected from the group consisting of O, N, S, CH2, NH, and Se,
wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids, and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms,
wherein R is1、R2、R3And R4Independently selected from CO, O2, SO2, SO, PO2, PO, CH, hydrogen or combinations of these and a) an alkyl of at least 3 carbons, an alkenyl of at least 3 carbons, an alkyl of at least 3 carbons substituted with a carboxy group, an alkenyl of at least 3 carbons substituted with a carboxy group, an alkyl of at least 3 carbons substituted with an amino group, an alkenyl of at least 3 carbons substituted with an amino group, an alkyl of at least 3 carbons substituted with both an amino group and a carboxy group, an alkenyl of at least 3 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens, b) a phenyl substituted with at least one carboxy group, a phenyl substituted with at least one halogen, a phenyl substituted with at least one alkoxy group, a phenyl substituted with at least one nitro group, a phenyl substituted with at least one sulfo group, a phenyl substituted with at least one amino group, a phenyl substituted with at least one alkylamino group, Phenyl substituted by at least one dialkylamino group, phenyl substituted by at least one hydroxyl group, phenyl substituted by at least one carbonyl group and phenyl substituted by at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxyl group, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy group, naphthyl substituted by at least one nitro group, naphthyl substituted by at least one sulfo group, naphthyl substituted by at least one amino group, naphthyl substituted by at least one alkylamino group, naphthyl substituted by at least one di-amino groupAlkylamino substituted naphthyl, naphthyl substituted by at least one hydroxyl, naphthyl substituted by at least one carbonyl and naphthyl substituted by at least one substituted carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxyl, heteroaryl substituted by at least one halogen, heteroaryl substituted by at least one alkoxy, heteroaryl substituted by at least one nitro, heteroaryl substituted by at least one sulfo, heteroaryl substituted by at least one amino, heteroaryl substituted by at least one alkylamino, heteroaryl substituted by at least one dialkylamino, heteroaryl substituted by at least one hydroxyl, heteroaryl substituted by at least one carbonyl and heteroaryl substituted by at least one substituted carbonyl, and e) a saccharide; a substituted sugar; d-galactose; substituted D-galactose; c3- [1,2,3]-triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino, substituted amino, imino, and substituted imino.
11. The method of any one of claims 1-10, wherein the halogen is a fluorine, chlorine, bromine, or iodine group.
13. The method of any one of claims 1-10 or 12, wherein the compound has binding affinity for galectin.
14. The method of any one of claims 1-10 or 12, wherein the compound has binding affinity for galectin-3.
15. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof.
16. The method of any one of claims 1-10 or 12, wherein in the step of administering, the compound is administered in combination with an active agent.
17. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound, a synergistic active agent, and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof.
18. The method of claim 15 or 16, wherein in the step of administering, the active agent is an immunomodulator, an anti-inflammatory drug, a vitamin, a nutraceutical, a supplement, or a combination thereof.
19. The method of any one of claims 1-10 or 12, for treating systemic insulin resistance associated with type 1 diabetes.
20. The method of any one of claims 1-10 or 12, for treating systemic insulin resistance associated with type 2 diabetes (T2 DM).
21. The method of any one of claims 1-10 or 12, for treating systemic insulin resistance associated with obesity, gestational diabetes, or prediabetes.
22. The method of any one of claims 1-10 or 12, wherein treatment with the compound restores sensitivity of cells to insulin activity.
23. The method of any one of claims 1-10 or 12, wherein the compound inhibits galectin-3 interaction with insulin receptors, thereby interfering with insulin binding and cellular glucose uptake mechanisms.
24. The method of any one of claims 1-10 or 12 for treating low grade inflammation resulting from insulin resistance in skeletal muscle and liver due to elevated levels of free fatty acids and triglycerides, leading to atherosclerotic vascular disease and NAFLD.
25. The method of any one of claims 1-10 or 12 for treating polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance.
26. The method of any one of claims 1-10 or 12 for treating diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGFb receptor pathways in renal chronic disease.
27. The method of any one of claims 1-10 or 12, wherein the compound inhibits overexpression of the TGF- β receptor signaling system and causes reduced renal function triggered by insulin resistance in a diabetic patient, and/or wherein the compound reverses a confirmed pathology of diabetic glomerulopathy.
28. The method according to any one of claims 1-10 or 12, for treating Obstructive Sleep Apnea (OSA) associated with insulin-resistant obesity and diabetes.
29. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound and a synergistically active antidiabetic agent.
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2018
- 2018-05-11 CN CN201880083771.8A patent/CN111527097A/en active Pending
- 2018-05-11 KR KR1020207015450A patent/KR20200081443A/en unknown
- 2018-05-11 CA CA3080128A patent/CA3080128A1/en active Pending
- 2018-05-11 WO PCT/US2018/032321 patent/WO2019089080A1/en unknown
- 2018-05-11 AU AU2018361991A patent/AU2018361991A1/en not_active Abandoned
- 2018-05-11 EP EP18874558.2A patent/EP3707149A1/en not_active Withdrawn
- 2018-05-11 JP JP2020524157A patent/JP2021501180A/en active Pending
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2020
- 2020-04-23 IL IL274162A patent/IL274162A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017152048A1 (en) * | 2016-03-04 | 2017-09-08 | Galectin Sciences, Llc | Selenogalactoside compounds for the prevention and treatment of diseases associated with galectin and the use thereof |
Non-Patent Citations (3)
Title |
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H.YILMAZ ET AL.: "Increased levels of galectin-3 were associated with prediabetes and diabetes:new risk factor?", 《J ENDOCRINOL INVEST》 * |
HAMDI PUSUROGLU ET AL.: "Galectin-3 is asspciated with coronary plaque burden and obstructive sleep apnoea syndrome severity", 《KARDIOLOGIA POLSKA》 * |
PINGPING LI ET AL.: "Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance", 《CELL》 * |
Also Published As
Publication number | Publication date |
---|---|
WO2019089080A1 (en) | 2019-05-09 |
CA3080128A1 (en) | 2019-05-09 |
EP3707149A1 (en) | 2020-09-16 |
JP2021501180A (en) | 2021-01-14 |
KR20200081443A (en) | 2020-07-07 |
AU2018361991A1 (en) | 2020-05-14 |
WO2019089080A9 (en) | 2020-07-23 |
IL274162A (en) | 2020-06-30 |
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Application publication date: 20200811 |