WO2019089080A9 - Selenogalactoside compounds for the treatment of systemic insulin resistance disorders and the use thereof - Google Patents

Selenogalactoside compounds for the treatment of systemic insulin resistance disorders and the use thereof Download PDF

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WO2019089080A9
WO2019089080A9 PCT/US2018/032321 US2018032321W WO2019089080A9 WO 2019089080 A9 WO2019089080 A9 WO 2019089080A9 US 2018032321 W US2018032321 W US 2018032321W WO 2019089080 A9 WO2019089080 A9 WO 2019089080A9
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group
substituted
heteroaryl
naphthyl
group substituted
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PCT/US2018/032321
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French (fr)
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WO2019089080A1 (en
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Peter G. Traber
Eliezer Zomer
Deirdre SLATE
Joseph M. Johnson
Ryan George
Sharon Shechter
Raphael NIR
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Galectin Sciences, Llc
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Priority to CN201880083771.8A priority Critical patent/CN111527097A/en
Priority to AU2018361991A priority patent/AU2018361991A1/en
Priority to CA3080128A priority patent/CA3080128A1/en
Priority to EP18874558.2A priority patent/EP3707149A1/en
Priority to JP2020524157A priority patent/JP2021501180A/en
Priority to KR1020207015450A priority patent/KR20200081443A/en
Publication of WO2019089080A1 publication Critical patent/WO2019089080A1/en
Priority to IL274162A priority patent/IL274162A/en
Publication of WO2019089080A9 publication Critical patent/WO2019089080A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • 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
    • C07H19/056—Triazole or tetrazole radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • aspects of the invention relate to compounds, pharmaceutical compositions, methods for the manufacturing of compounds and methods for treatment of metabolic disorders mediated at least in part by one or more galactose binding proteins also referred to as Galectins.
  • Galectins are a family of S-type lectins that bind beta-galactose glycan containing glycoproteins. To date, fifteen mammalian Galectins have been isolated. Galectins regulate different biological processes such as diabetes, inflammation, fibrogenesis, metabolic disorders, cancer progression, metastasis, apoptosis, and immune evasion.
  • aspects of the invention relate to compounds and compositions comprising a compound in an acceptable pharmaceutical carrier for parenteral or enteral administration, for use in therapeutic formulations.
  • the composition can be administered orally or topically or parenterally via an intravenous or subcutaneous route.
  • aspects of the invention relate to compounds, compositions and methods of treating various disorders in which lectin proteins play a role in the pathogenesis, including but not limited to treating systemic insulin resistance.
  • the compound can reverse galectin-3 binding to the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance.
  • the systemic insulin resistance is associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes.
  • the compound restores sensitivity of cells to insulin activity.
  • the compound inhibits galectin-3 interaction with Insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanism.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance, and the compensatory hyperinsulinemia.
  • PCOS polycystic ovarian syndrome
  • aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGFb Receptor pathway in kidney chronic disease
  • the compound can inhibit the overexpression of TGFb receptor signaling system triggered by insulin resistance in diabetic and cause decline in renal function, and can reverse the established lesions of diabetic glomerulopathy.
  • the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof in some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound is administered with one or more anti diabetic drug.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • the compounds or compositions of the invention that bind to insulin receptor also identified as IR, INSR, CD220, HHF5.
  • aspects of the invention relate to compounds, compositions and methods of treating diseases caused by disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ).
  • aspects of the invention relate to compounds, compositions and methods of treating diseases associated with the Transforming Growth Factor Beta signaling pathway.
  • aspects of the invention relate to compounds or compositions for the treatment of a diversity of chronic inflammatory diseases, fibrotic diseases, and cancers.
  • the compound is capable of mimicking glycoprotein interactions with lectins or galectin proteins which are known to modulate the pathophysiological pathways leading to immune recognition, inflammation, fibrogenesis, angiogenesis, cancer progression and metastasis.
  • the compound comprises pyranosyl and/or furanosyl structures bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl.
  • specific aromatic substitutions can be added to the galactose core or heteroglycoside core to further enhance the affinity of the selenium bound pyranosyl and/or furanosyl structures.
  • aromatic substitutions can enhance the interaction of the compound with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc%) composing the carbohydrate- recognition-domains (CRD) of the lectins and thus strengthen the association and binding specificity.
  • the compound can comprise monosaccharides, disaccharides, oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom (Se) on the anomeric carbon of the galactose or of the heteroglycoside.
  • Se selenium atom
  • the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds and wherein the selenium is bound to the anomeric carbon of the galactose. In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds and wherein the selenium is bound to the anomeric carbon of the galactose. Yet in other embodiments, the compound can be an asymmetric digalactoside. For example, the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compound is a symmetric galactoside having one or more selenium on the anomeric carbon of the galactose.
  • the galactoside has one or more selenium bound to the anomeric carbon of the galactose and one or more sulfur bound to the selenium.
  • the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compounds containing the selenium containing molecules render the compound metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins or galectins known to recognize carbohydrates.
  • the monogalactoside, digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic or S-glycosidic bond.
  • the compound is a compound having Formula
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, SO3, PO2, amino acid, an hydrophobic linear and cydic hydrophobic hydrocarbons derivatives induding heterocydic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives induding heterocydic substitutions of 3 or more atoms,
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of CO, O2, S O2, PO2, PO, CH, Hydrogen, or combination of these and, a) an alkyl group of at least 3 cartons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 cartons substituted with a carboxy group, an alkenyl group of at least 3 cartons substituted with a carboxy group, an alkyl group of at least 3 cartons substituted with an amino group, an alkenyl group of at least 3 cartons substituted with an amino group, an alkyl group of at least 3 cartons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a
  • the compound has the general Formula (3) or Formula (4) or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocartons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • R 1 and R 2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 cartons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted
  • X is Se, Se-Se, Se-S; S-Se, Se-S02, or S02-Se,
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acid an combinations thereof
  • Z is selected from the group consisting of O, S, N, CH, Se, S, , P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • R 2 , R3 and R 4 are independently selected from the group consisting of CO, 02, S02, SO, P02, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a
  • the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
  • the compound is in a free form.
  • the free form is an anhydrate.
  • the free form is a solvate, such as a hydrate.
  • the compound is in a crystalline form.
  • compositions comprising the compound of the invention and optionally a pharmaceutically acceptable additive, such as adjuvant, carrier, excipient or combinations thereof.
  • a pharmaceutically acceptable additive such as adjuvant, carrier, excipient or combinations thereof.
  • the pharmaceutical composition comprising the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as adjuvant, carrier, excipient or combinations thereof.
  • the compounds of the present invention bind to one or more galectins. In some embodiments, the compound binds to Galectin-3, Galectin-1 , Galectin 8, and/or Galectin 9.
  • the compounds of the present invention have high selectivity and affinity for Galectin-3. In some embodiments, the compounds of the present invention have an affinity of about 1 nM to about 50 mM for Galectin-3.
  • Aspects of the invention relate to compositions or compounds that can be used in the treatment of diseases. Aspects of the invention relate to compositions or compounds that can be used in the treatment of diseases in which galectins are at least in part involved in the pathogenesis. Other aspects of the invention relate to methods of treatment of a disease in a subject in need thereof.
  • Some aspects of the invention relates to methods of treating insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.
  • Some aspects of the invention relates to methods of treating insulin resistance, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound can be used in conjunction with an active agent.
  • the active agent is an immunomodulatory, an anti-inflammatory drug, a vitamin, a nutraceutical drug, a supplement, or combinations thereof.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFbi (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFbi -Receptor) so as to recover normal regenerative activity in tissues.
  • TGFbi Transforming Growth Factor beta 1
  • TGFbi -Receptor receptor
  • Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
  • Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a Galectin, such as Galectin-3 binding to an Insulin-Receptor or TGFbi -receptor in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) to a subject in need thereof.
  • a Galectin such as Galectin-3 binding to an Insulin-Receptor or TGFbi -receptor in a human
  • Some aspects of the present 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 for treating a disorder relating to the binding of a galectin in a subject in need thereof.
  • Some aspects of the present invention relate to a compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating a disorder relating to the binding of galectin-3 to a ligand in a subject in need thereof.
  • 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 a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3, to a ligand in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
  • the method of treatment is for systemic insulin resistance.
  • Figure 1 depicts a high-definition 3D structure of Galectin-3 Carbohydrate Recognition Domain (CRD) binding pocket with 3 potential sites of interaction.
  • CCD Carbohydrate Recognition Domain
  • Figure 2 depicts the CRD pocket location in the Galectin-3 C-terminal with bound lactose unit.
  • Figure 3 depicts a map of the Galectin-3 CRD site vicinity - potential cooperative amino-acids for enhanced binding.
  • Figure 4 depicts the synthesis of Selenium galactoside compounds according to some embodiments.
  • Figure 5A depicts a Fluorescent Polarization Assay Format which detects compounds that bind specifically to the CRD according to some embodiments.
  • Figure 5B depicts a Fluorescence Resonance Energy Transfer analytical assay (FRET Format) for screening compounds that inhibit Galectin-3 interaction with its Glycoprotein-ligand (for example TGFbl -Receptor FRET format) according to some embodiments.
  • FRET Format Fluorescence Resonance Energy Transfer analytical assay
  • Figure 6A depicts the inhibition of Galectin binding moiety using a specific anti-Galectin-3 monoclonal antibodies binding assay (ELISA format) according to some embodiments.
  • Figure 6B depicts a functional assay to screen compounds that inhibit the Galectin-3 interaction with its Glycoprotein-ligand (for example Insulin-Receptor ELISA format) according to some embodiments.
  • Glycoprotein-ligand for example Insulin-Receptor ELISA format
  • Figure 7 provides examples of Compounds IC50 by Fluorescent Polarization - CRD specific assay of compounds according to some embodiments.
  • Figure 8 provides examples of Compounds IC50 by the Insulin-Receptor- Galectin-3 ELISA format assays according to some embodiments.
  • Figure 9 provides examples of Compounds IC50 by the TGFbl -Receptor- Galectin-3 ELISA format assay according to some embodiments.
  • aspects of the invention relate to compositions of mono, disaccharides and oligosaccharides of Galactose (or heteroglycoside) core bound to a selenium atom (Se) on the anomeric carbon of the Galactose (or heteroglycoside).
  • the Se containing molecules render them metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins known to recognize carbohydrates.
  • the specific aromatic substitutions added to the galactose core further enhance the affinity of the Selenium bound pyranosyl and/or furanosyl structures by enhancing their interaction with amino acid residues (e.g.
  • the composition or the compound can be used in the treatment of nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic conditions or cancers.
  • the composition can be used in the treatment of liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis.
  • the composition or the compound is capable of enhancing anti-fibrosis activity in organs, including but not limited to, liver, kidney, lung, and heart.
  • the composition or the compound can be used in treatment of inflammatory disorders of the vasculature including atherosclerosis and pulmonary hypertension.
  • the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy.
  • the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
  • the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
  • aspects of the invention relates to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.
  • aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
  • aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH).
  • the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
  • aspects of the invention relates to a composition or a compound used in treating or a method of treating inflammatory and autoimmune disorders in which galectins are at least in part involved in the pathogenesis including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization.
  • the composition or a compound can be used to treat primary and secondary cancers.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • anti-CTLA2, anti-PD1 , anti-PDL1 checkpoint inhibitors
  • other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • a therapeutically effective amount of the compound or of the composition can be compatible and effective in combination with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other pharmaceuticals and nutraceuticals drugs or supplement, or combinations thereof without limitation.
  • Galectins also known as galaptins or S-lectins
  • S-lectins are a family of lectins which bind beta-galactoside.
  • Galectin as a general name was proposed in 1994 for a family of animal lectins (Barondes, S. H., et al.: Galectins: a family of animal beta- galactoside-binding lectins. Cell 76, 597-598, 1994).
  • the family is defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides and sharing certain sequence elements.
  • CCD characteristic carbohydrate recognition domain
  • galectins into three subgroups including: (1 ) galectins having a single CRD, (2) galectins having two CRDs joined by a linker peptide, and (3) a group with one member (galectin-3) which has one CRD joined to a different type of N-terminal domain.
  • the galectin carbohydrate recognition domain is a beta- sandwich of about 135 amino acids. The two sheets are slightly bent with 6 strands forming the concave side, also called the S-face, and 5 strands forming the convex side, the F-face).
  • the concave side forms a groove in which carbohydrate is bound (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). “Introduction to galectins”. Glycoconj. J. 19 (7-9): 433-40).
  • the carbohydrate domain binds to galactose residues associated with glycoproteins.
  • Galectins show an affinity for galactose residues attached to other organic compounds, such as in lactose [(P-D-Galactosido)-D- glucose], N-acetyl-lactosamine, poly-N-acetyllactosamine, galactomannans, or fragments of pectins.
  • lactose (P-D-Galactosido)-D- glucose]
  • N-acetyl-lactosamine N-acetyl-lactosamine
  • poly-N-acetyllactosamine poly-N-acetyllactosamine
  • galactomannans or fragments of pectins.
  • At least fifteen mammalian galectin proteins have been identified which have one or two carbohydrate domains in tandem.
  • Galectin proteins are found in the intracellular space where they have been assigned a number of functions and they are also are secreted into the extracellular space where they have different functions. In the extracellular space, galectin proteins can have multiple functions that are mediated by their interaction with galactose containing glycoproteins including promoting interactions between glycoproteins that may modulate function or, in the case of integral membrane glycoprotein receptors, modification of cellular signaling (Sato et al “Galectins as danger signals in host-pathogen and host-tumor interactions: new members of the growing group of “Alarmins.” In“Galectins,” (Klyosov, et al eds.), John Wiley and Sons, 1 15-145, 2008, Liu et al“Galectins in acute and chronic inflammation,” Ann.
  • Galectin proteins in the extracellular space can additionally promote cell-cell and cell matrix interactions (Wang et al.,“Nuclear and cytoplasmic localization of galectin-1 and galectin-3 and their roles in pre-mRNA splicing.” In“Galectins” (Klyosov et al eds.), John Wiley and Sons, 87-95, 2008).
  • galectin functions appear to be more related to protein-protein interactions, although intracellular vesicle trafficking appears to be related to interaction with glycoproteins.
  • Galectins have been shown to have domains which promote homodimerization. Thus, galectins are capable of acting as a “molecular glue” between glycoproteins. Galectins are found in multiple cellular compartments, including the nucleus and cytoplasm, and are secreted into the extracellular space where they interact with cell surface and extracellular matrix glycoproteins. The mechanism of molecular interactions can depend on the localization. While galectins can interact with glycoproteins in the extracellular space, the interactions of galectin with other proteins in the intracellular space generally occurs via protein domains. In the extracellular space the association of cell surface receptors may increase or decrease receptor signaling or the ability to interact with ligands.
  • Galectin proteins are markedly increased in a number of animal and human disease states, including but not limited to diseases associated with inflammation, fibrosis, autoimmunity, and neoplasia. Galectins have been directly implicated in the disease pathogenesis, as described below.
  • diseases states that may be dependent on galectins include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic disorders, asthma, dermatitis, autoimmune disease, inflammatory and degenerative arthritis, immune- mediated neurological disease, fibrosis of multiple organs (including but not limited to liver, lung, kidney, pancreas, and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular inflammatory disease, a large variety of cancers.
  • galectins are important regulatory molecules in modulating the response of immune cells to vaccination, exogenous pathogens and cancer cells.
  • Galectin proteins such as galectin-1 and galectin-3 have been shown to be markedly increased in inflammation, fibrotic disorders, and neoplasia (Ito et al. “Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment”, Cancer Metastasis Rev. PMID: 22706847 (2012), Nangia- Makker et al.
  • Galectin-3 binding and metastasis Methods Mol. Biol. 878: 251-266, 2012, Canesin et al. Galectin-3 expression is associated with bladder cancer progression and clinical outcome,” T umour Biol. 31 : 277-285, 2010, Wanninger et al. “Systemic and hepatic vein galectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function,” Cytokine. 55: 435-40, 201 1 ).
  • galectins particularly galectin-1 (gal-1 ) and galectin-3 (gal-3), are directly involved in the pathogenesis of these classes of disease (Toussaint et al.,“Galectin-1 , a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion.”, Mol. Cancer. 1 1 :32, 2012, Liu et al 2012, Newlaczyl et al.,“Galectin-3— a jack-of-all-trades in cancer,” Cancer Lett.
  • 201 1 Banh et al., “Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis,” Cancer Res. 71 : 4423-31 , 201 1 , Lefranc et al.,“Galectin-1 mediated biochemical controls of melanoma and glioma aggressive behavior,” World J. Biol. Chem. 2: 193-201 , 201 1 , Forsman et al., “Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis,” Arthritis Reum.
  • Galectin-3 testing may be useful in helping physicians determine which patients are at higher risk of hospitalization or death.
  • the BGM Galectin-3® Test is an in vitro diagnostic device that quantitatively measures Galectin-3 in serum or plasma and can be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure. Measure of the concentration of endogenous protein Galectin-3 can be used to predict or monitor disease progression or therapeutic efficacy in patients treated with cardiac resynchronization therapy (see US 8,672,857).
  • Galectin-3 has been shown to be elevated in patients with metabolic disorders and in obesity population 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 an enduring disease which can be resolved but can be prevented by taking care. It is one of the commonly found metabolic syndromes in the world. Diabetes mellitus mainly associates with central nervous system and peripheral nervous system which are chronic complications. Diabetes mellitus is a commonly seen metabolic syndrome of diabetes where the body cannot use glucose and stores in blood which may damage kidneys, nerves, heart, eyes, and other complications.
  • Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS).
  • MetS is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
  • Insulin resistance the key feature of type 2 diabetes could develop in someone with type 1 diabetes designate clinically as Double diabetes. Someone with double diabetes will always have type 1 diabetes present but with complication of insulin resistance. The most common reason for developing insulin resistance is obesity and whilst type 1 diabetes is not itself brought on by obesity.
  • Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
  • Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decrease in insulin sensitivity.
  • the insulin receptor is a transmembrane protein that is activated by bound insulin, IGF-I, IGF-II and belongs to the class of tyrosine kinase receptors. Insulin receptor plays a key role in the regulation of glucose homeostasis, that when dysfunction or metabolic impairment may result in a range of clinical manifestations including but not limited to diabetes.
  • the insulin receptor is encoded by a single gene INSR, which during transcription may result in either IR-A or IR-B isoforms. Post-translational these isoform result in the formation of a proteolytically cleaved a and b subunits, which combine to form the final active -320 kDa transmembrane insulin receptor.
  • Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that controls cell growth and differentiation.
  • Insulin receptor substrate is the common intermediate, which include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiates signal transduction. However, when serine 307 is phosphorylated, signaling is diminished.
  • Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
  • Some aspects of the invention relate to compounds and use of compounds that inhibit Galectin-3 to treat insulin resistance.
  • aspects of the invention relates to novel compounds that mimic the natural ligand of galectin proteins.
  • the compound mimics the natural ligand of galectin-3.
  • the compound mimics the natural ligand of galectin-1 .
  • the compound mimics the natural ligand of galectin-8.
  • the compound mimics the natural ligand of galectin-9.
  • the compound has a mono, di or oligomer structure composed of Galactose-Se core bound to the anomeric carbon on the galactose and which serves as a linker to the rest of the molecule.
  • the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD.
  • the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind in “site B” of the galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD.
  • the compounds can have substitutions that interact with site A and/or site C to further improve the association with the CRD and enhance their potential as a therapeutic targeted to galectin-dependent pathology.
  • the substituents can be selected through in-silico analysis (computer assisted molecular modeling) as described herein.
  • the substituents can be further screened using binding assay with the galectin protein of interest.
  • the compounds can be screened using a galectin-3 binding assay and/or an in-vitro inflammatory and fibrotic model of activated cultured macrophages (see Chavez-Galán, L. et a! , Immunol. 2015; 8: 263).
  • the compounds comprise one or more specific substitutions of the core Galactose-Se.
  • the core Galactose-Se can be substituted with specific substituents that interact with residues located within the CRD. Such substituents can dramatically increase the association and potential potency of the compound as well as the 'drugability' characteristic.
  • Selenium has five possible oxidation states (-2, 0, +2, +4 and +6), and therefore is well represented in a variety of compounds with diverse chemical properties. Furthermore, selenium can be present in the place of sulphur in virtually all sulphur compounds, inorganic as well as organic.
  • selenium compounds organic and inorganic, are readily absorbed from the diet and transported to the liver - the prime organ for selenium metabolism.
  • the general metabolism of selenium compounds follows three major routes depending on the chemical properties, that is, redox-active selenium compounds, precursors of methylselenol and seleno-amino acids.
  • Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but can also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity (Misra, 2015). Sodium Selenite has been studied as a cytotoxic agent in Advanced Carcinoma (SECAR, see Brodin, Ola et al., 2015).
  • aspects of the invention relates to compounds comprising pyranosyl and/or furanosyl structures bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl.
  • specific aromatic substitutions can be added to the galactose core or heteroglycoside core to further enhance the affinity of the selenium bound pyranosyl and/or furanosyl structures.
  • aromatic substitutions can enhance the interaction of the compound with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc%) composing the carbohydrate- recognition-domains (CRD) of the lectins and thus strengthen the association and binding specificity.
  • the compound comprises monosaccharides, disaccharides and oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom on the anomeric carbon of the galactose or of the heteroglycoside.
  • the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and wherein the selenium is bound to the anomeric carbon of the galactose. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds and wherein the selenium is bound to the anomeric carbon of the galactose. Yet in other embodiments, the compound can be an asymmetric digalactoside. For example, the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compound is a symmetric galactoside wherein a single galactoside having one or more selenium on the anomeric carbon of the galactose.
  • the galactoside has one or more selenium bound to the anomeric carbon of the galactose and one or more sulfur bound to the selenium.
  • the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compounds containing the Se containing molecules render the compound metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins or galectins known to recognize carbohydrates.
  • the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic bond.
  • the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an S-glycosidic bond.
  • aspects of the invention relate to compounds based on galactoside structure with a Selenium bridge [X] to another galactose, hydroxyl cyclohexane, aromatic moiety, alkyl, aryl, amine, or amide.
  • alkyl group is meant to comprise from 1 to 12 carbon atoms, for example 1 to 7 or 1 to 4 carbon atoms or 3 to 7 carbon atoms.
  • the alkyl group may be straight- or branched-chain.
  • the alkyl group may also form a cycle comprising from 3 to 7 carbon atoms, preferably 3, 4, 5, 6, or 7 carbon atoms.
  • alkyl encompasses any of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1- methylcyclopropyl.
  • alkenyl group is meant to comprise from 2 to 12, for example 2 to 7 carbon atoms or 3 to 7 carbon atoms.
  • the alkenyl group comprises at least one double bond.
  • the alkenyl group encompasses any of vinyl, allyl, but-1-enyl, but-2-enyl, 2,2-dimethylethenyl, 2,2- dimethylprop-1 -enyl, pent-1 -enyl, pent-2-enyl, 2,3-dimethyibut-1-enyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, prop-1 , 2-dienyl, 4 ⁇ methylhex-1-enyl, cycloprop-1 -enyl group, and others.
  • alkoxy group relates to an alkoxy group containing 1-12 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments the alkoxy group contains 1 to 7 or 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms.
  • alkoxy group encompasses a methoxy group, an ethoxy group, a propoxy group, a isopropoxy group, a n-butoxy group, a sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 3-methylbutoxy group, 2,2-dimethylpropoxy group, n- hexoxy group, 2-methylpentoxy group, 2,2-dimethylbutoxy group 2,3-dimethylbutoxy group, n-heptoxy group, 2-methylhexoxy group, 2,2-dimethylpentoxy group, 2,3- dimethylpentoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and 1-methylcyclopropyloxy group.
  • aryl group is meant to comprise from 3 to 12 carbon atoms.
  • Said aryl group may be a phenyl group or a naphthyl group.
  • the above-mentioned groups may naturally be substituted with any other known substituents within the art of organic chemistry.
  • the groups may also be substituted with two or more of the said substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro.
  • Alkyl groups are as defined above containing 1 to 7 carbon atoms.
  • Alkenyl are as defined above containing 2 to 7 carbon atoms, preferably 2 to 4.
  • Alkoxy is as defined below containing 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may contain an unsaturated carbon atom. Combinations of substituents can be present such as trifluoromethyl.
  • heteroaryl group is meant to comprise any aryl group comprising from 4 to 18 carbon atoms, wherein at least one atom of the ring is a heteroatom, i.e. not a carbon.
  • the heteroaryl group may be a pyridine, or an indole group.
  • the above-mentioned groups may be substituted with any other known substituents within the art of organic chemistry.
  • the groups may also be substituted with two or more of the substituents.
  • substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups.
  • Halogen substituents can be bromo, fluoro, iodo, and chloro.
  • Alkyl groups are as defined above containing 1 to 7 carbon atoms.
  • Alkenyl are as defined above containing 2 to 7 carbon atoms, for example 2 to 4.
  • Alkoxy is as defined below containing 1 to 7 carbon atoms, for example 1 to 4 carbon atoms, which may contain an unsaturated carbon atom.
  • the compound is a monomeric-selenium polyhydroxylated- cycloalkanes compound having Formula (1 ) or Formula (2) or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, NH, CH2, Se, S, S02, P02, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • R 2 , and R 3 are independently selected from the group consisting of CO, 02, S02, P02, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl
  • the compound is a dimeric-polyhydroxylated- cycloalkane compound. In some embodiment, the compound is an oligomeric selenium polyhydroxylated - cycloalkane compound with 3 or more units.
  • the compound has the general formulas (3) and (4) below or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • R 2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at
  • alkyl group relates to an alkyl group containing 1-7 carbon atoms, which may include one or more unsaturated carbon atoms.
  • the alkyl group contains 1 -4 carbon atoms, which may include one or more unsaturated carbon atoms.
  • the carbon atoms in the alkyl group may form a straight or branched chain.
  • the carbon atoms in said alkyl group may also form a cycle containing 3, 4, 5, 6, or 7 carbon atoms.
  • alkyl group used herein encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.
  • the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
  • the compound has the general formulas (5) and (6) below or a pharmaceutically acceptable salt or solvate thereof:
  • X is Se, Se-Se, Se-S; S-Se, Se-S02, or S02-Se,
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, P, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof
  • Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms
  • R 2 , R3 and R 4 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phen
  • the halogen is a fluoro, a chloro, a bromo or an iodo group.
  • the compound has the following formulas as shown in Table 1 and is an inhibitor of galectln-3.
  • Table 1 shows non-limiting examples of monomeric Se Galactosides.
  • the compound has the following formulas as shown in Table 2 and is an inhibitor of galectin-3.
  • Table 2 shows non-limiting examples of Di-Se saccharides.
  • the compound has the following formulas shown in Table 3 and is an inhibitor of ga!ectin-3
  • Table 3 shows non-limiting examples of oligo-Se saccharides.
  • Tetrameric Se-galactosides are expected to have higher affinity to the CRD versus the trimeric structure due to additional potential interaction of hydroxyl groups with amino-acids in the CRD vicinity (see Example 14).
  • the galactose-selenium compounds described herein have an enhanced stability as its structure is less prone to hydrolysis (metabolism) and oxidation, e.g. aromatic ring without substitutions, Carbon-Oxygen systems, Carbone-Nitrogen system etc.
  • Standard assays to evaluate the binding ability of the ligand toward target molecules are known in the art, including for example, ELISAs, western blots and RIAs. Suitable assays are described in detail herein.
  • the binding kinetics e.g., binding affinity
  • Biacore analysis Assays to evaluate the effects of the compounds on functional properties of the galectin are described in further detail herein.
  • One way to determine protein-ligand binding affinity uses a structure- based model that can predict the interaction of the protein -ligand complex that results when the ligand binds to the protein. Such structures may be studied by x-ray crystallography. In some embodiments, compounds of interest can be screened“in silico” to predict the ligand’s affinity to the lectin or galectin proteins using any scoring system known in the art.
  • a computational modeling can be used to facilitate structure-based drug design.
  • the in-sllico model also enables to visually inspect the protein-compound interaction, conformational strain and possible steric clashes and avoid them.
  • the protein-ligand affinity can be scored using a Glide (Schrodinger, Portland OR).
  • GlideScore is a quantitative measurement that provides an estimate for a ligand binding free energy.
  • the GlideScore data showed that the introduction of Se to the anomeric carbon (G-625) on the galactose scores the same as the thiogalactoside (TD-139, also referred as G-240).
  • the results also showed that the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) have comparable overall estimated predictor of free energy.
  • the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) are expected to have comparable affinity to galectin-3 and inhibitor effects.
  • the Se atom allows the rest of the molecule (for example G-625) to fulfill the interactions seen with TD-139, but with a superior affinity to Galectin-3 vs. TD-139 as was shown in the Elisa based assay and fluorescent polarization assay.
  • the selenogalactoside of Formula (1 ) has an affinity to galectin-3 that is at least twice or at least three time stronger than TD-139.
  • the selenogalactosides of the present invention have an affinity to galectin-3 that is at least twice or at least three times stronger than the corresponding thiogalactoside.
  • the 'drugability' characteristic as defined by the computational structure analysis considers compounds: (1 ) stereoisomerization, (2) position of the hydroxyl groups on the sugar (e.g. axial or equatorial) and (3) position and nature of substituents.
  • the present invention relates to compounds that are galactose-based bound to a Selenium atom bound to the anomeric carbon, serving as a linker to the rest of the molecule.
  • the compounds can have substituents capable of, or designed to, reach amino acids that are part of the binding site which were known and unknown to play a role in ligand's binding.
  • substituents capable of, or designed to, reach amino acids that are part of the binding site which were known and unknown to play a role in ligand's binding.
  • galectins bind the monosaccharide galactose with dissociation constants in the millimolar range. It has been shown that addition of N-acetyl glucosamine to galactose can provide additional interaction with neighboring sites boosts the compound affinity to galectin-3 over 10 fold (Bachhawat-Sikder Et al. FEBS Lett. 2001 Jun 29;500(1-2):75-9).
  • Human Galectin-3 cavity is shallow with high solvent accessibility. It is very hydrophilic but capable of forming cation-p interactions with Arg144 and possibly Trp181 (Magnani 2009, Logan 201 1 ). It has been shown that upon ligand's binding, Arg144 moves 3.5A upwards from the protein surface to make a pocket for the Arene-Arginine interaction. It should be noted that Arg144 is absent in other galectin, e.g. Gal-1 , Gal-9 and this is being exploited in our in-silico model. Similarly, potency can be improved by exploiting cation-p interactions with the surface residue of Arg186. For example, triazole substitution at C3 of galactose has been reported to increase Galectin 3 affinity (Salameh BA et al. Bioorg. Med. Chem. Lett. 2005 Jul 15; 15(14):3344-6.)
  • Tryptophan 181 at subsite C is conserved throughout the galectin family.
  • a p - p stacking interaction between the Trp181 (W181 ) side chain and a carbohydrate residue (galactose being the natural carbohydrate occupant) accommodated within subsite C occurs in all reported galectin-saccharide complexes.
  • the side chain of Arg144 is capable of adopting different conformations due to its inherent flexibility that could contribute to greater affinity via an arginine-arene interaction (a cation- p or tt - p stacking interaction) with the aromatic moiety.
  • galectin s key residues that affect ligand affinity were identified using computational alanine scanning mutagenesis (ASM) or an“in- silico-alanine-scan”.
  • ASM computational alanine scanning mutagenesis
  • ASM can be performed by sequential replacement of individual residues by alanine to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of an individual amino acid to the functionality of the protein.
  • Galectin-3 R186S abolishes carbohydrate interactions.
  • the R186S was shown to have has a selectively lost affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, and has lost the ability to activate neutrophil leukocytes and intracellular targeting into vesicles (see Salomonsson E. et al. , J Biol Chem. 2010 Nov 5;285(45):35079- 91.)
  • Table 5 shows the in-silico Alanine scan comparison results using TD- 139 Compound
  • Table 6 shows the in-silico Alanine scan comparison results using G- 625 Compound having Formula 1
  • ** dG>100 suggests increase in ligand binding upon mutation to Alanine while dG ⁇ 100 suggests decrease in ligand binding upon mutation.
  • residue N174 play an important role in the binding of both TD-139 and G-625 compounds. Without being bound to the theory it is possible that residue N174 may help in positioning the Galactose core in 'the optimal orientation’ that will enable the CRD site to recognize carbohydrate like framework of the oxygens.
  • the compounds of this invention may be prepared by the following general methods and procedures. It should be appreciated that where typical or preferred process conditions (e.g. reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants, solvents used and pH etc., but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • process conditions e.g. reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH etc.
  • the compound was synthetized using the synthetic route shown in FIG. 4
  • compound G-625 was prepared as detailed in Example 10.
  • aspects of the invention relate to the use of the compounds described herein for the manufacture of medicaments. Some embodiments relate to the compounds or the use of the compounds having formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof. Some embodiments relate to the compounds or the use of the compounds of Tables 1-4.
  • compositions comprising one or more of the compounds described herein.
  • the pharmaceutical compositions comprise one or more of the following: pharmaceutically acceptable adjuvant, diluent, excipient, and carrier.
  • pharmaceutically acceptable carrier refers to a carrier or adjuvant that may be administered to a subject (e.g., a patient), together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount or an effective mount of the compound.
  • “Pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media. The use of such media and compounds for pharmaceutically active substances is well known in the art.
  • the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration (e.g., by injection or infusion).
  • the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • compositions comprising the compound of the invention and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprising the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprising the compound of Tables 1-4 or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprises a compound described herein as active ingredient together with a pharmaceutically acceptable adjuvant, diluent, excipient or carrier.
  • a pharmaceutical composition can comprise from 1 to 99 weight % of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier and from 1 to 99 weight % of a compound described herein.
  • the adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention are pharmaceutically acceptable, i.e. are compatible with the compounds and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof.
  • the adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person within the art.
  • An effective oral dose of the compound of the present invention to an experimental animal or human may be formulated with a variety of excipients and additives that enhance the absorption of the compound via the stomach and small intestine.
  • the pharmaceutical composition of the present invention may comprise two or more compounds of the present invention.
  • the composition may also be used together with other medicaments within the art for the treatment of related disorders.
  • the pharmaceutical composition comprising one or more compounds described herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder, or, for administration via the eye, intra-ocuiariy, intravitreaiiy or corneally.
  • the pharmaceutical composition comprising one or more compounds described herein may be in the form of, for example, tablets, capsules, powders, solutions for injection, solutions for spraying, ointments, transdermal patches or suppositories.
  • Some aspects of the present invention relate to pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • An effective oral dose could be 10 times and up to 100 times the amount of the effective parental dose.
  • An effective oral dose may be given daily, in one or divided doses or twice, three times weekly, or monthly.
  • the compounds described herein can be co- administered with one or more other therapeutic agents.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention (e.g., sequentially, e.g., on different overlapping schedules with the administration of the compound of the invention.
  • these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • these agents can be given as a separate dose that is administered at about the same time that the compound of the invention.
  • compositions include a combination of the compound of this invention and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • a therapeutically effective amount of the compound or of the composition can be compatible and effective in combination with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other pharmaceuticals and nutraceuticals drugs or supplement, or combinations thereof without limitation.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or 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 combinations thereof.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1- 4 or a pharmaceutically acceptable salt or solvate thereof is administered with one or more anti diabetic drug.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • the active agent is an antidiabetic drug.
  • the term“synergistic effect” refers to the correlated action of two or more agents of the present invention so that the combined action is greater than the sum of each acting separately.
  • the compounds of the present invention and the active agent can be administered simultaneously or sequentially.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • anti-CTLA2, anti-PD1 , anti-PDL1 checkpoint inhibitors
  • other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • anti-CTLA2, anti-PD1 , anti-PDL1 checkpoint inhibitors
  • other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
  • galectin is gaiectin-3
  • Some aspects of the invention relate to the method of treating various disorders relating to the binding of a galectin to a ligand.
  • the methods comprise administering in a subject in need thereof a therapeutically effective amount of at least one compound described herein.
  • the subject in need thereof is a human having high levels of ga!ectin-3.
  • Levels of galectin, for example gaiectin-3 can be quantified using any methods known in the art.
  • Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFbl -Receptor) so as to recover normal regenerative activity in tissues.
  • TGFbl Transforming Growth Factor beta 1
  • TGFbl -Receptor receptor
  • Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
  • Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a Galectin, such as Galectin-3 binding to an Insulin-Receptor or TGFbl -receptor in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1-4 or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
  • a Galectin such as Galectin-3 binding to an Insulin-Receptor or TGFbl -receptor in a human
  • the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1-4 or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
  • aspects of the invention relate to compounds, compositions and methods of treating various disorders in which lectin proteins play a role in the pathogenesis, including but not limited to treating systemic insulin resistance.
  • the compound can reverse galectin-3 binding to the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance.
  • the systemic insulin resistance is associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes.
  • the compound restores sensitivity of cells to insulin activity.
  • the compound inhibits galectin-3 interaction with Insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanism.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance, and the compensatory hyperinsulinemia which affects some 65-70% of women with PCOS.
  • PCOS polycystic ovarian syndrome
  • aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TOF ⁇ Receptor pathway in kidney chronic disease
  • the compound can inhibit the overexpression of TGFb receptor signaling system triggered by Insulin resistance in diabetic and cause decline in renal function, and can reverse the established lesions of diabetic glomerulopathy.
  • the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound is administered with one or more anti diabetic drug.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • the compounds or compositions of the invention that bind to insulin receptor also identified as IR, INSR, CD220, HHF5.
  • Aspects of the invention relate to compounds, compositions and methods of treating diseases caused by disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ).
  • the disorder is an inflammatory disorder, for example inflammatory bowel disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
  • inflammatory disorder for example inflammatory bowel disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
  • the disorder is fibrosis, for example liver fibrosis, pulmonary fibrosis, kidney fibrosis, heart fibrosis or fibrosis of any organ compromising the normal function of the organ.
  • the disorder is cancer.
  • the disorder is an autoimmune disease such as rheumatoid arthritis and multiple sclerosis.
  • the disorder is heart disease or heart failure.
  • the disorder is a metabolic disorder, for example diabetes.
  • the disorder relating is pathological angiogenesis, such as ocular angiogenesis, disease or conditions associated with ocular angiogenesis and cancer.
  • the composition or the compound can be used in the treatment of nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic conditions or cancers.
  • the composition can be used in the treatment of liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis.
  • the composition or the compound is capable of enhancing anti-fibrosis activity in organs, including but not limited to, liver, kidney, lung, and heart.
  • the composition or the compound can be used in treatment of inflammatory disorders of the vasculature including atherosclerosis and pulmonary hypertension.
  • the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy.
  • the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
  • the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
  • aspects of the invention relates to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.
  • aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
  • aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH).
  • the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
  • aspects of the invention relates to a composition or a compound used in treating or a method of treating inflammatory and autoimmune disorders in which galectins are at least in part involved in the pathogenesis including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • neoplastic conditions e.g. benign or malignant neoplastic diseases
  • the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization.
  • the composition or a compound can be used to treat primary and secondary cancers.
  • the compound is a monomeric-selenium polyhydroxylated- cycloalkanes compound or a pharmaceutically acceptable salt or solvate thereof:
  • Z is a carbohydrate or linkage consisting of O, S, C, NH, CH2, Se, amino acid to R 2 and R 3 ;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acid, and a combination thereof.
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50-200 D.
  • the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group,
  • the compound is a dimeric-polyhydroxylated- cycloalkane compound.
  • the compound has the general or a pharmaceutically acceptable salt or solvate thereof:
  • X is Se, Se-Se or Se-S;
  • Z is independently selected from a carbohydrate (composing, for example, an oligomeric Se-galactoside) or linkage consisting of O, S, C, NH, CH2, Se, and amino acid to R 3 and R 4 ;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, and amino acid
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, Hydrogen, and hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50- 200 D.
  • the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group,
  • X is Se, Se-Se or Se-S;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y, and Z are independently selected from the group consisting of O, S, C, NH, CH2, Se, and amino acid;
  • R 2 are independently selected from the group consisting of CO, SO 2 , SO, PO2, PO, CH, Hydrogen, hydrophobic linear and cyclic hydrocarbon including heterocyclic substitutions of molecular weight of 50-200 D including, but not limited to:
  • an alkyl group of at least 4 carbons an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens;
  • a phenyl group substituted with at least one car boxy group a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group,
  • a naphthyl group a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group; and
  • a heteroaryl group a heteroaryl group substituted with at least one carboxy 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,
  • a saccharide a substituted saccharide; D-galactose; substituted D-galactose; C3- [1 ,2,3]-triaZol-1 -yl-substituted D-galactose; hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group.
  • Example 1 Compound inhibition of Galectin binding to labeled probes
  • Fluorescein-labeled probes have been developed which bind to Galectin 3 and other Galectin proteins and these probes have been used to establish assays (FIGS. 5A & 5B) that measure the binding affinity of ligands for the Galectin proteins using Fluorescence Polarization (Sorme P, et al. Anal Biochem. 2004 Nov 1 ;334(1 ):36-47).
  • IC50 concentration at 50% inhibition
  • the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 pM. In some embodiments, the IC50 is from about 0.5 mM to about 10 mM. In some embodiments, the IC50 is from about 5 mM to about 40 mM.
  • G-625 a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-
  • G-625 has single selenide bridge between two Aryl- triazole-galactosides, (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • G-626 a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-
  • G-625 has double selenide bridge between two Aryl- triazole-galactosides (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • FRET assay fluorescent resonance energy transfer assays were developed for evaluating the interaction of Galectin proteins, including but not limited to Galectin-3, with a model fluorescent-labeled probe (see FIG. 5B).
  • compounds described herein avidly bind to Galectin-3, as well as other Galectin proteins, using this assay and displace the probe with high affinity, with IC 50 ’s (concentration at 50% inhibition) of between about 5 hM to about 40 mM.
  • the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM.
  • the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 mM. In some embodiments, the IC50 is from about 0.5 mM to about 10 mM. In some embodiments, the IC50 is from about 5 mM to about 40 mM.
  • Example 3 Compound inhibition of qalectin binding to physiologic ligands
  • Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS), Mets is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
  • T2DM diabetes mellitus
  • MetS Metabolic Syndrome
  • Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. I. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
  • Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decreased in insulin sensitivity. Inhibition of Galectin-3 could be a new drug target to treat insulin resistance.
  • Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that control cell growth and differentiation.
  • Insulin receptor substrate is the common intermediate, which include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiate signal transduction. However, when serine 307 is phosphorylated, signaling is diminished.
  • Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
  • G-625 a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1-yl)-1-seleno-.
  • G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
  • G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazoM -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1-yl)-1-seleno-.
  • G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the TGF-b receptor - galectin-3 (FIG. 9).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ), showed an inhibitory activity in the TGF-b receptor - galectin-3 interaction (FIG. 9).
  • Example 4 Compound binding to amino acid residues in qalectin proteins
  • Heteronuclear NMR spectroscopy is used to evaluate the interaction of compounds described herein with galectin molecules, including but not limited to galectin-3, to assess the interaction residues on the galectin-3 molecule.
  • NMR experiments are carried out at 30°C on Bruker 600 MHz, 700 MHz or 850 MHz spectrometers equipped with H/C/N triple-resonance probes and x/y/z triple-axis pulse field gradient units.
  • a gradient sensitivity-enhanced version of two-dimensional 1 H- 15 N HSQC is applied with 256 (t1 ) x 2048 (t2) complex data points in nitrogen and proton dimensions, respectively.
  • Raw data are converted and processed by using NMRPipe and were analyzed by using NMRview.
  • Example 5 Cellular activity of cytokine activity related to qalectin binding inhibition
  • Example 1 describes the ability of compounds of this application to inhibit the binding of physiologic ligands to galectin molecules. In the experiments of this example, the functional implications of those binding interactions were evaluated. [00246] One of the interactions with galectin-3 that is inhibited by the compounds described herein was TGF-b receptor. Therefore, experiments were done to evaluate the effect of compounds on TGR-b receptor activity in cell lines. Various TGF-b responsive cell lines, including but not limited to LX-2 and THP-1 cells, were treated with TGF-b and response of the cells was measured by looking at activation of second messenger systems, including but not limited to phosphorylation of various intracellular SMAD proteins.
  • MCF-7 cells were resuspended in culture media containing 4X Pen/Strep and 0.25% Fetal Bovine Serum (Gibco lot# 1202161 ).
  • Tested compound was diluted serially in assay media as above, usually at a range of 100 mg/ml to 20 ng/mL
  • HTB-38 cells were resuspended in culture media containing 8 ng/ml h-IFN- gamma, 4X Pen/Strep and 10% Fetal Bovine Serum (Gibco lot# 1260930).
  • Tested compound was diluted serially in assay media as above, usually in range of 100 mg/ml to 20 ng/mL
  • Cellular motility assays are performed to evaluate the physiological significance of inhibiting the interaction of galectin-3 with various integrin and other cell surface molecules defined in Example 1.
  • Cellular studies are performed using multiple cell lines in a semi-permeable membrane separated well apparatus. Treatment of cells with compounds described herein is found to inhibit cellular motility, confirming that the binding interaction inhibition described in Example 1 has a physiological role in cellular models.
  • a model of macrophage polarization was set up, starting from THP-1 monocytes culture which is differentiated into inflammatory macrophages using PMA (Phorbol 12-myristate 13-acetate) for 2-4 days. Once differentiated (M0 macrophages), the macrophages were induced with LPS or LPS and IFN-gamma for macrophage activation (M1 ) to inflammatory stage for 1 -3 days. Array of cytokines and chemokines were analyzed to confirm the polarization of THP-1 -derived macrophages to inflammatory stage.
  • PMA Phorbol 12-myristate 13-acetate
  • the impact of the anti-galectin 3 compounds on macrophage polarization was assessed first by monitoring cell viability using a colorimetric method (using a tetrazolium reagent) to determine the number of viable cells in proliferation or cytotoxicity assays (Promega, The CellTiter 96® AQueous One Solution Cell Proliferation Assay which contains a novel tetrazolium compound [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES)) and inflammatory stage evaluated by a quantitatively measure of the chemokine Monocyte Chemoattractant Protein-1 (MCP-1 / CCL2), a key protein that regulates migration and infiltration of monocytes/macrophages in cellular process of inflammation.
  • THP-1 cells were stimulated by microbial endotoxin which transforms the cells to inflammatory macrophages (M1 ) which secret inflammatory cytokines like Monocyte Chemoattractant Protein-1 (MCP-1 ).
  • M1 macrophages
  • MCP-1 Monocyte Chemoattractant Protein-1
  • THP-1 cells were cultured in media containing Gentamicin
  • THP-1 cells are transfer to wells in a 96 well plate 2,000 cells/well for 2 days incubation in assay media containing 10 ng/ml PMA
  • Compounds described herein are evaluated for physicochemical properties, including but not limited to solubility (Thermodynamic and Kinetic method), various pH changes, solubility in biorelevant medium (FaSSIF, FaSSGF, FeSSIF), Log D (Octanol/water and Cyclohexane/water), chemical stability in plasma, and blood partitioning.
  • solubility Thermodynamic and Kinetic method
  • biorelevant medium FaSSIF, FaSSGF, FeSSIF
  • Log D Octanol/water and Cyclohexane/water
  • chemical stability in plasma and blood partitioning.
  • Compounds described herein are evaluated for animal pharmacokinetic properties, including but not limited to pharmacokinetics by various routes viz., oral, intravenous, intraperitoneal, subcutaneous in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (New Zealand white), dogs (Beagle), Cynomolgus monkeys, etc., tissue distribution, brain to plasma ratio, biliary excretion, and mass balance.
  • routes viz., oral, intravenous, intraperitoneal, subcutaneous in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (New Zealand white), dogs (Beagle), Cynomolgus monkeys, etc., tissue distribution, brain to plasma ratio, biliary excretion, and mass balance.
  • Compounds described herein are evaluated for protein binding, including but not limited to plasma protein binding (ultra-Filtration and Equilibrium Dialysis) and microsomal protein binding.
  • 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 microsome metabolism, S-9 fraction metabolism, effect on cryopreserved hepatocyte, plasma stability, and GSH trapping.
  • Compounds described herein are evaluated for metabolite identification, including but not limited to identification in vitro (microsomes, S9 and hepatocytes) and in vivo samples.
  • Example 9 Cell culture adipocyte model
  • 3T3-L1 adipocytes were cultured with various doses of insulin (10 nM to 100 nM) to cause chronic insulin exposure or 0.1 M to 1 M dexamethasone (DEX) for 8 to 24h at 37 °C or with 1 to 20 ng/ml TNF at 37 °C for 48 h in full DMEM medium. The medium was replaced twice a day with fresh medium containing TNF. After insulin resistance treatment, cells were washed and then serum starved for 1-2 h prior to insulin stimulation and assessment of insulin- regulated kinases and processes. It has been previously shown that this protocol is adequate to return the cells to their baseline level of GLUT4 translocation (Hoehn, K.
  • the cell pellet was resuspended in 1 1 ml of MM.
  • the cells were plated at 20,000 cells per 10OmI in a 96-well plate.
  • the cells were grown to confluency at 37°C in 5% C02 with medium replacement every 2 days. Because of the weak adherence of these cells during differentiation, cells were plated on collagen coated plates (Corning, Cat.# 356650). Medium removal and addition was performed at the slowest pipetting speeds possible.
  • 3T3L1 adipocytes were assayed as follows:
  • the medium was replaced with 100mI DMEM without serum or glucose (Life Technologies, Cat. # 11966) containing a range of insulin concentrations.
  • the cells were incubated for 1 hour at 37 e C in 5% CO2.
  • Luminescence was recorded with 0.3-1 second integration on a luminometer to evaluate the cellular effect of Galectin-3 on glucose uptake.
  • adipocytes cells Differentiation of adipocytes cells was monitored by various well- defined insulin related activation markers, including expression of Insulin Receptor (IR) and its activation by insulin, but not limited to IR kinase activity within minutes of exposing to insulin. Inhibition of this insulin activation by treatment with Galectin-3. The effect of Galectin-3 on IR was monitored also by rate of glucose uptake.
  • IR Insulin Receptor
  • Step-1
  • reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a pad of celite bed, washed with EtOAc, dried (Na 2 S0 4 ) and concentrated in vacuo and the residue was washed with Et 2 O (10 mL) to afford the title compound (7) as a white solid (164 mg, 94%).

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Abstract

Aspects of the invention relate to novel synthetic compounds having a binding affinity with galectin proteins for the treatment of systemic insulin resistance disorders.

Description

SELENOGALACTOSIDE COMPOUNDS FOR THE TREATMENT OF SYSTEMIC INSULIN RESISTANCE DISORDERS AND THE USE THEREOF
INVENTORS
Peter G. Traber, Eliezer Zomer, Deirdre Slate, Joseph M. Johnson, Ryan George,
Sharon Shechter and Raphael Nir
RELATED APPLICATION(S)
[001] This application claims the benefit of and priority to U.S. Provisional Application Serial No. 62/579,343, filed October 31 , 2017, the entire disclosure is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[002] Aspects of the invention relate to compounds, pharmaceutical compositions, methods for the manufacturing of compounds and methods for treatment of metabolic disorders mediated at least in part by one or more galactose binding proteins also referred to as Galectins.
BACKGROUND OF THE INVENTION
[003] Galectins are a family of S-type lectins that bind beta-galactose glycan containing glycoproteins. To date, fifteen mammalian Galectins have been isolated. Galectins regulate different biological processes such as diabetes, inflammation, fibrogenesis, metabolic disorders, cancer progression, metastasis, apoptosis, and immune evasion.
SUMMARY OF THE INVENTION
[004] Aspects of the invention relate to compounds and compositions comprising a compound in an acceptable pharmaceutical carrier for parenteral or enteral administration, for use in therapeutic formulations. In some embodiments, the composition can be administered orally or topically or parenterally via an intravenous or subcutaneous route. [005] Aspects of the invention relate to compounds, compositions and methods of treating various disorders in which lectin proteins play a role in the pathogenesis, including but not limited to treating systemic insulin resistance. In some embodiments, the compound can reverse galectin-3 binding to the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
[006] Aspects of the invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance. In some embodiments, the systemic insulin resistance is associated with obesity where elevated galectin-3 interacts with insulin receptor. In some embodiments, treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
[007] Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes. Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM). Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores sensitivity of cells to insulin activity. In some embodiments, the compound inhibits galectin-3 interaction with Insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanism. Aspects of the invention relate to compounds, compositions and methods for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD. Aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance, and the compensatory hyperinsulinemia. Aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGFb Receptor pathway in kidney chronic disease in some embodiments, the compound can inhibit the overexpression of TGFb receptor signaling system triggered by insulin resistance in diabetic and cause decline in renal function, and can reverse the established lesions of diabetic glomerulopathy. [008] In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof in some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof. In some embodiments, the compound is administered with one or more anti diabetic drug. In some embodiments, administration of the compound of the present invention and the active agent produces a synergistic effect.
[009] Aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor. In some embodiments, treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
[0010] In some embodiments, the compounds or compositions of the invention that bind to insulin receptor (also identified as IR, INSR, CD220, HHF5).
[0011] Aspects of the invention relate to compounds, compositions and methods of treating diseases caused by disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ).
[0012] Aspects of the invention relate to compounds, compositions and methods of treating diseases associated with the Transforming Growth Factor Beta signaling pathway.
[0013] Aspects of the invention relate to compounds or compositions for the treatment of a diversity of chronic inflammatory diseases, fibrotic diseases, and cancers. In some embodiments, the compound is capable of mimicking glycoprotein interactions with lectins or galectin proteins which are known to modulate the pathophysiological pathways leading to immune recognition, inflammation, fibrogenesis, angiogenesis, cancer progression and metastasis.
[0014] In some embodiments, the compound comprises pyranosyl and/or furanosyl structures bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl.
[0015] In some embodiments, specific aromatic substitutions can be added to the galactose core or heteroglycoside core to further enhance the affinity of the selenium bound pyranosyl and/or furanosyl structures. Such aromatic substitutions can enhance the interaction of the compound with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc...) composing the carbohydrate- recognition-domains (CRD) of the lectins and thus strengthen the association and binding specificity.
[0016] In some embodiments, the compound can comprise monosaccharides, disaccharides, oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom (Se) on the anomeric carbon of the galactose or of the heteroglycoside.
[0017] In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds and wherein the selenium is bound to the anomeric carbon of the galactose. In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds and wherein the selenium is bound to the anomeric carbon of the galactose. Yet in other embodiments, the compound can be an asymmetric digalactoside. For example, the compound can have different aromatic or aliphatic substitutions on the galactose core.
[0018] In some embodiments, the compound is a symmetric galactoside having one or more selenium on the anomeric carbon of the galactose. In some embodiments, the galactoside has one or more selenium bound to the anomeric carbon of the galactose and one or more sulfur bound to the selenium. In some embodiments, the compound can have different aromatic or aliphatic substitutions on the galactose core.
[0019] Without being bound to the theory, it is believed that the compounds containing the selenium containing molecules render the compound metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins or galectins known to recognize carbohydrates.
[0020] In some embodiments, the monogalactoside, digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic or S-glycosidic bond. [0021] In some embodiments, the compound is a compound having Formula
[1] or Formula (2) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
wherein X is 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 acid, an hydrophobic linear and cydic hydrophobic hydrocarbons derivatives induding heterocydic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives induding heterocydic substitutions of 3 or more atoms,
wherein R1, R2, and R3 are independently selected from the group consisting of CO, O2, S O2, PO2, PO, CH, Hydrogen, or combination of these and, a) an alkyl group of at least 3 cartons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 cartons substituted with a carboxy group, an alkenyl group of at least 3 cartons substituted with a carboxy group, an alkyl group of at least 3 cartons substituted with an amino group, an alkenyl group of at least 3 cartons substituted with an amino group, an alkyl group of at least 3 cartons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triazol-1 -yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group.
[0022] In some embodiments, the compound has the general Formula (3) or Formula (4) or a pharmaceutically acceptable salt or solvate thereof:
Formula (3)
Figure imgf000009_0001
wherein X is 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 acid, an hydrophobic linear and cyclic hydrophobic hydrocartons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein n£ 24,
wherein R1 and R2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 cartons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triaZol-1 -yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group. In some embodiments, n=1. In other embodiments, n=3. [0023] In some embodiments, the compound is a compound having Formula (5) or Formula (6) or a pharmaceutically acceptable salt or solvate thereof:
Formula (5)
Figure imgf000011_0002
wherein X is Se, Se-Se, Se-S; S-Se, Se-S02, or S02-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 acid an combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, , P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein
Figure imgf000011_0001
R2, R3 and R4 are independently selected from the group consisting of CO, 02, S02, SO, P02, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D- galactose, C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group. [0024] In some embodiments, the halogen is a fluoro, a chloro, a bromo or an iodo group.
[0025] In some embodiments, the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
[0026] Aspect the present invention relates to a compound of formula (5) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000013_0001
Formula 7
[0027] In some embodiments, the compound is in a free form. In some embodiments, the free form is an anhydrate. In some embodiments, the free form is a solvate, such as a hydrate.
[0028] In some embodiments, the compound is in a crystalline form.
[0029] Some aspects of the present invention relate to a pharmaceutical composition comprising the compound of the invention and optionally a pharmaceutically acceptable additive, such as adjuvant, carrier, excipient or combinations thereof. In some embodiments, the pharmaceutical composition comprising the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as adjuvant, carrier, excipient or combinations thereof.
[0030] In some embodiments, the compounds of the present invention bind to one or more galectins. In some embodiments, the compound binds to Galectin-3, Galectin-1 , Galectin 8, and/or Galectin 9.
[0031] In some embodiments, the compounds of the present invention have high selectivity and affinity for Galectin-3. In some embodiments, the compounds of the present invention have an affinity of about 1 nM to about 50 mM for Galectin-3. [0032] Aspects of the invention relate to compositions or compounds that can be used in the treatment of diseases. Aspects of the invention relate to compositions or compounds that can be used in the treatment of diseases in which galectins are at least in part involved in the pathogenesis. Other aspects of the invention relate to methods of treatment of a disease in a subject in need thereof.
[0033] Some aspects of the invention relates to methods of treating insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.
[0034] Some aspects of the invention relates to methods of treating insulin resistance, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.
[0035] In some embodiments, the compound can be used in conjunction with an active agent. In some embodiments, the active agent is an immunomodulatory, an anti-inflammatory drug, a vitamin, a nutraceutical drug, a supplement, or combinations thereof. In some embodiments, administration of the compound of the present invention and the active agent produces a synergistic effect.
[0036] Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFbi (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFbi -Receptor) so as to recover normal regenerative activity in tissues.
[0037] Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
[0038] Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a Galectin, such as Galectin-3 binding to an Insulin-Receptor or TGFbi -receptor in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) to a subject in need thereof.
[0039] Some aspects of the present 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 for treating a disorder relating to the binding of a galectin in a subject in need thereof. Some aspects of the present invention relate to a compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating a disorder relating to the binding of galectin-3 to a ligand in a subject in need thereof.
[0040] In some embodiments, the subject in need thereof is a mammal. In some embodiments, the subject in need thereof is a human.
[0041] Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3, to a ligand in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof. In some embodiments, the method of treatment is for systemic insulin resistance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] 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.
[0043] The present invention will be further explained with reference to the attached drawings, wherein like structures are referred to by like numerals throughout the several views. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the present invention.
[0044] Figure 1 depicts a high-definition 3D structure of Galectin-3 Carbohydrate Recognition Domain (CRD) binding pocket with 3 potential sites of interaction.
[0045] Figure 2 depicts the CRD pocket location in the Galectin-3 C-terminal with bound lactose unit. [0046] Figure 3 depicts a map of the Galectin-3 CRD site vicinity - potential cooperative amino-acids for enhanced binding.
[0047] Figure 4 depicts the synthesis of Selenium galactoside compounds according to some embodiments.
[0048] Figure 5A depicts a Fluorescent Polarization Assay Format which detects compounds that bind specifically to the CRD according to some embodiments.
[0049] Figure 5B depicts a Fluorescence Resonance Energy Transfer analytical assay (FRET Format) for screening compounds that inhibit Galectin-3 interaction with its Glycoprotein-ligand (for example TGFbl -Receptor FRET format) according to some embodiments.
[0050] Figure 6A depicts the inhibition of Galectin binding moiety using a specific anti-Galectin-3 monoclonal antibodies binding assay (ELISA format) according to some embodiments.
[0051] Figure 6B depicts a functional assay to screen compounds that inhibit the Galectin-3 interaction with its Glycoprotein-ligand (for example Insulin-Receptor ELISA format) according to some embodiments.
[0052] Figure 7 provides examples of Compounds IC50 by Fluorescent Polarization - CRD specific assay of compounds according to some embodiments.
[0053] Figure 8 provides examples of Compounds IC50 by the Insulin-Receptor- Galectin-3 ELISA format assays according to some embodiments.
[0054] Figure 9 provides examples of Compounds IC50 by the TGFbl -Receptor- Galectin-3 ELISA format assay according to some embodiments.
DETAILED DESCRIPTION OF THE INVENTION
[0055] Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention is intended to be illustrative, and not restrictive. Further, the figures are not necessarily to scale, some features may be exaggerated to show details of particular components. In addition, any measurements, specifications and the like shown in the figures are intended to be 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.
[0056] Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application.
[0057] 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(s), though it may. Furthermore, the phrases“in another embodiment” and“in some other embodiments” as used herein do not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.
[0058] In addition, 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. In addition, throughout the specification, the meaning of "a," "an," and "the" include plural references.
[0059] Unless otherwise specified, all percentages expressed herein are weight/weight.
[0060] Aspects of the invention relate to compositions of mono, disaccharides and oligosaccharides of Galactose (or heteroglycoside) core bound to a selenium atom (Se) on the anomeric carbon of the Galactose (or heteroglycoside). In some embodiments, the Se containing molecules render them metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins known to recognize carbohydrates. In some embodiments, the specific aromatic substitutions added to the galactose core further enhance the affinity of the Selenium bound pyranosyl and/or furanosyl structures by enhancing their interaction with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc...) composing the carbohydrate-recognition-domains (CRD) of the lectins and thus strengthening the association and binding specificity. [0061] In some embodiments, the composition or the compound can be used in the treatment of nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic conditions or cancers.
[0062] In some embodiments, the composition can be used in the treatment of liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis.
[0063] In some embodiments, the composition or the compound is capable of enhancing anti-fibrosis activity in organs, including but not limited to, liver, kidney, lung, and heart.
[0064] In some embodiments, the composition or the compound can be used in treatment of inflammatory disorders of the vasculature including atherosclerosis and pulmonary hypertension.
[0065] In some embodiments, the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy.
[0066] In some embodiments, the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
[0067] In some embodiments, the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
[0068] Aspects of the invention relates to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.
[0069] Aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
[0070] Aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH). In other aspects, the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
[0071] Aspects of the invention relates to a composition or a compound used in treating or a method of treating inflammatory and autoimmune disorders in which galectins are at least in part involved in the pathogenesis including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
[0072] Aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins. In some embodiments, the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins. In some embodiments, the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the composition or a compound can be used to treat primary and secondary cancers.
[0073] Aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
In some embodiments, a therapeutically effective amount of the compound or of the composition can be compatible and effective in combination with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other pharmaceuticals and nutraceuticals drugs or supplement, or combinations thereof without limitation.
Galectins
[0074] Galectins (also known as galaptins or S-lectins) are a family of lectins which bind beta-galactoside. Galectin as a general name was proposed in 1994 for a family of animal lectins (Barondes, S. H., et al.: Galectins: a family of animal beta- galactoside-binding lectins. Cell 76, 597-598, 1994). The family is defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides and sharing certain sequence elements. Further structural characterization segments the galectins into three subgroups including: (1 ) galectins having a single CRD, (2) galectins having two CRDs joined by a linker peptide, and (3) a group with one member (galectin-3) which has one CRD joined to a different type of N-terminal domain. The galectin carbohydrate recognition domain is a beta- sandwich of about 135 amino acids. The two sheets are slightly bent with 6 strands forming the concave side, also called the S-face, and 5 strands forming the convex side, the F-face). The concave side forms a groove in which carbohydrate is bound (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). “Introduction to galectins”. Glycoconj. J. 19 (7-9): 433-40).
[0075] A wide variety of biological phenomena have been shown to be related to galectins, including development, differentiation, morphogenesis, tumor metastasis, apoptosis, RNA splicing, and many others.
[0076] Generally, the carbohydrate domain binds to galactose residues associated with glycoproteins. Galectins show an affinity for galactose residues attached to other organic compounds, such as in lactose [(P-D-Galactosido)-D- glucose], N-acetyl-lactosamine, poly-N-acetyllactosamine, galactomannans, or fragments of pectins. However, it should be noted that galactose by itself does not bind to galectins.
[0077] Plant polysaccharides like pectin and modified pectin have been shown to bind to galectin proteins presumably on the basis of containing galactose residues that are presented in the context of a macromolecule, in this case a complex carbohydrate rather than a glycoprotein in the case of animal cells.
[0078] At least fifteen mammalian galectin proteins have been identified which have one or two carbohydrate domains in tandem.
[0079] Galectin proteins are found in the intracellular space where they have been assigned a number of functions and they are also are secreted into the extracellular space where they have different functions. In the extracellular space, galectin proteins can have multiple functions that are mediated by their interaction with galactose containing glycoproteins including promoting interactions between glycoproteins that may modulate function or, in the case of integral membrane glycoprotein receptors, modification of cellular signaling (Sato et al “Galectins as danger signals in host-pathogen and host-tumor interactions: new members of the growing group of “Alarmins.” In“Galectins,” (Klyosov, et al eds.), John Wiley and Sons, 1 15-145, 2008, Liu et al“Galectins in acute and chronic inflammation,” Ann. N.Y. Acad. Sci. 1253: 80-91 , 2012). Galectin proteins in the extracellular space can additionally promote cell-cell and cell matrix interactions (Wang et al.,“Nuclear and cytoplasmic localization of galectin-1 and galectin-3 and their roles in pre-mRNA splicing.” In“Galectins” (Klyosov et al eds.), John Wiley and Sons, 87-95, 2008). In regards to intracellular space, galectin functions appear to be more related to protein-protein interactions, although intracellular vesicle trafficking appears to be related to interaction with glycoproteins.
[0080] Galectins have been shown to have domains which promote homodimerization. Thus, galectins are capable of acting as a “molecular glue” between glycoproteins. Galectins are found in multiple cellular compartments, including the nucleus and cytoplasm, and are secreted into the extracellular space where they interact with cell surface and extracellular matrix glycoproteins. The mechanism of molecular interactions can depend on the localization. While galectins can interact with glycoproteins in the extracellular space, the interactions of galectin with other proteins in the intracellular space generally occurs via protein domains. In the extracellular space the association of cell surface receptors may increase or decrease receptor signaling or the ability to interact with ligands.
[0081] Galectin proteins are markedly increased in a number of animal and human disease states, including but not limited to diseases associated with inflammation, fibrosis, autoimmunity, and neoplasia. Galectins have been directly implicated in the disease pathogenesis, as described below. For example, diseases states that may be dependent on galectins include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic disorders, asthma, dermatitis, autoimmune disease, inflammatory and degenerative arthritis, immune- mediated neurological disease, fibrosis of multiple organs (including but not limited to liver, lung, kidney, pancreas, and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular inflammatory disease, a large variety of cancers.
[0082] In addition to disease states, galectins are important regulatory molecules in modulating the response of immune cells to vaccination, exogenous pathogens and cancer cells.
[0083] One of skill in the art will appreciate that compounds that can bind to galectins and/or alter galectin's affinity for glycoproteins, reduce hetero- or homo- typic interactions between galectins, or otherwise alter the function, synthesis, or metabolism of galectin proteins may have important therapeutic effects in galectin- dependent diseases. [0084] Galectin proteins, such as galectin-1 and galectin-3 have been shown to be markedly increased in inflammation, fibrotic disorders, and neoplasia (Ito et al. “Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment”, Cancer Metastasis Rev. PMID: 22706847 (2012), Nangia- Makker et al. Galectin-3 binding and metastasis,” Methods Mol. Biol. 878: 251-266, 2012, Canesin et al. Galectin-3 expression is associated with bladder cancer progression and clinical outcome,” T umour Biol. 31 : 277-285, 2010, Wanninger et al. “Systemic and hepatic vein galectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function,” Cytokine. 55: 435-40, 201 1 ). Moreover, experiments have shown that galectins, particularly galectin-1 (gal-1 ) and galectin-3 (gal-3), are directly involved in the pathogenesis of these classes of disease (Toussaint et al.,“Galectin-1 , a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion.”, Mol. Cancer. 1 1 :32, 2012, Liu et al 2012, Newlaczyl et al.,“Galectin-3— a jack-of-all-trades in cancer,” Cancer Lett. 313: 123-128, 201 1 , Banh et al., “Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis,” Cancer Res. 71 : 4423-31 , 201 1 , Lefranc et al.,“Galectin-1 mediated biochemical controls of melanoma and glioma aggressive behavior,” World J. Biol. Chem. 2: 193-201 , 201 1 , Forsman et al., “Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis,” Arthritis Reum. 63: 445-454, 201 1 , de Boer et al.,“Galectin-3 in cardiac remodeling and heart failure,” Curr. Heart Fail. Rep. 7, 1-8, 2010, Ueland et al., “Galectin-3 in heart failure: high levels are associated with all-cause mortality,” Int J. Cardiol. 150: 361-364, 201 1 , Ohshima et al.,“Galectin 3 and its binding protein in rheumatoid arthritis,” Arthritis Rheum. 48: 2788-2795, 2003).
[0085] High levels of serum Galectin-3 have been shown to be associated with some human diseases, such as a more aggressive form of heart failure, which make identification of high-risk patients using Galectin-3 testing an important part of patient care. Galectin-3 testing may be useful in helping physicians determine which patients are at higher risk of hospitalization or death. For example, the BGM Galectin-3® Test is an in vitro diagnostic device that quantitatively measures Galectin-3 in serum or plasma and can be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure. Measure of the concentration of endogenous protein Galectin-3 can be used to predict or monitor disease progression or therapeutic efficacy in patients treated with cardiac resynchronization therapy (see US 8,672,857).
[0086] Galectin-3 has been shown to be elevated in patients with metabolic disorders and in obesity population 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 an enduring disease which can be resolved but can be prevented by taking care. It is one of the commonly found metabolic syndromes in the world. Diabetes mellitus mainly associates with central nervous system and peripheral nervous system which are chronic complications. Diabetes mellitus is a commonly seen metabolic syndrome of diabetes where the body cannot use glucose and stores in blood which may damage kidneys, nerves, heart, eyes, and other complications.
Insulin resistance
[0087] Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS). MetS is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
[0088] Insulin resistance, the key feature of type 2 diabetes could develop in someone with type 1 diabetes designate clinically as Double diabetes. Someone with double diabetes will always have type 1 diabetes present but with complication of insulin resistance. The most common reason for developing insulin resistance is obesity and whilst type 1 diabetes is not itself brought on by obesity.
[0089] People with type 1 diabetes are able to become obese and suffer from insulin resistance as much as anyone else.
[0090] Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
[0091] Recent studies indicate that Galectin-3 plasma levels are significantly elevated in human and animal obesity models.
[0092] In obesity, macrophages and other immune cells have been reported to recruited to insulin target tissues, and promoting a chronic inflammatory state and insulin resistance. Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decrease in insulin sensitivity.
[0093] The insulin receptor is a transmembrane protein that is activated by bound insulin, IGF-I, IGF-II and belongs to the class of tyrosine kinase receptors. Insulin receptor plays a key role in the regulation of glucose homeostasis, that when dysfunction or metabolic impairment may result in a range of clinical manifestations including but not limited to diabetes. The insulin receptor is encoded by a single gene INSR, which during transcription may result in either IR-A or IR-B isoforms. Post-translational these isoform result in the formation of a proteolytically cleaved a and b subunits, which combine to form the final active -320 kDa transmembrane insulin receptor.
[0094] Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that controls cell growth and differentiation. Insulin receptor substrate (IRS) is the common intermediate, which include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiates signal transduction. However, when serine 307 is phosphorylated, signaling is diminished. Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
[0095] Some aspects of the invention relate to compounds and use of compounds that inhibit Galectin-3 to treat insulin resistance. Galectin Inhibitors
[0096] Natural oligosaccharide ligands capable of binding to galectin-1 and/or galectin-3, for example, modified forms of pectins and galactomannan derived from Guar-gum have been described (see WO 2013040316, US 201 10294755, WO 2015138438). Synthetic digalactosides like lactose, N-acetyllactosamine (LacNAc) and thiolactose effective against pulmonary fibrosis and other fibrotic disease (WO 2014067986 A1 , incorporated herein by reference in their entireties).
[0097] Advances in protein crystallography and availability of high definition 3D structure of the carbohydrate recognition domain (CRD) of many galectins have generated many derivatives with enhanced affinity to the CRD having a greater affinity than galactose or lactose (WO 2014067986, incorporated herein by reference in its entirety). These compounds were shown to be effective for treatment of an animal model of lung fibrosis which is thought to mimic human idiopathic pulmonary fibrosis (IPF). For example, a thio-digalactopyranosyl substituted with 3- fiuorophenyl-2,3-triazol groups (TD-139) has been reported to bind to galectin 3 and to be effective in in a mouse model of lung fibrosis. The compound required pulmonary administration using intra-tracheal instillation or nebulizers (see US8703720, US7700763, US7638623 and US7230096, incorporated herein by reference in their entireties).
[0098] Aspects of the invention relates to novel compounds that mimic the natural ligand of galectin proteins. In some embodiments, the compound mimics the natural ligand of galectin-3. In some embodiments, the compound mimics the natural ligand of galectin-1 . In some embodiments, the compound mimics the natural ligand of galectin-8. In some embodiments, the compound mimics the natural ligand of galectin-9.
[0099] In some embodiments, the compound has a mono, di or oligomer structure composed of Galactose-Se core bound to the anomeric carbon on the galactose and which serves as a linker to the rest of the molecule. In some embodiments, the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD. In some embodiments, the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind in “site B” of the galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD.
[00100] According to some aspects, the compounds can have substitutions that interact with site A and/or site C to further improve the association with the CRD and enhance their potential as a therapeutic targeted to galectin-dependent pathology. In some embodiments, the substituents can be selected through in-silico analysis (computer assisted molecular modeling) as described herein. In some embodiments, the substituents can be further screened using binding assay with the galectin protein of interest. For example, the compounds can be screened using a galectin-3 binding assay and/or an in-vitro inflammatory and fibrotic model of activated cultured macrophages (see Chavez-Galán, L. et a! , Immunol. 2015; 8: 263).
[00101] According to some aspects, the compounds comprise one or more specific substitutions of the core Galactose-Se. For example, the core Galactose-Se can be substituted with specific substituents that interact with residues located within the CRD. Such substituents can dramatically increase the association and potential potency of the compound as well as the 'drugability' characteristic.
Selenium
[00102] Selenium has five possible oxidation states (-2, 0, +2, +4 and +6), and therefore is well represented in a variety of compounds with diverse chemical properties. Furthermore, selenium can be present in the place of sulphur in virtually all sulphur compounds, inorganic as well as organic.
[00103] Most selenium compounds, organic and inorganic, are readily absorbed from the diet and transported to the liver - the prime organ for selenium metabolism. The general metabolism of selenium compounds follows three major routes depending on the chemical properties, that is, redox-active selenium compounds, precursors of methylselenol and seleno-amino acids.
[00104] Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but can also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity (Misra, 2015). Sodium Selenite has been studied as a cytotoxic agent in Advanced Carcinoma (SECAR, see Brodin, Ola et al., 2015).
Galactoside-selenium compounds
[00105] Aspects of the invention relates to compounds comprising pyranosyl and/or furanosyl structures bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl.
[00106] In some embodiments, specific aromatic substitutions can be added to the galactose core or heteroglycoside core to further enhance the affinity of the selenium bound pyranosyl and/or furanosyl structures. Such aromatic substitutions can enhance the interaction of the compound with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc...) composing the carbohydrate- recognition-domains (CRD) of the lectins and thus strengthen the association and binding specificity.
[00107] In some embodiments, the compound comprises monosaccharides, disaccharides and oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom on the anomeric carbon of the galactose or of the heteroglycoside.
[00108] In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and wherein the selenium is bound to the anomeric carbon of the galactose. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds and wherein the selenium is bound to the anomeric carbon of the galactose. Yet in other embodiments, the compound can be an asymmetric digalactoside. For example, the compound can have different aromatic or aliphatic substitutions on the galactose core.
[00109] In some embodiments, the compound is a symmetric galactoside wherein a single galactoside having one or more selenium on the anomeric carbon of the galactose. In some embodiments, the galactoside has one or more selenium bound to the anomeric carbon of the galactose and one or more sulfur bound to the selenium. In some embodiments, the compound can have different aromatic or aliphatic substitutions on the galactose core.
[00110] Without being bound to the theory, it is believed that the compounds containing the Se containing molecules render the compound metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins or galectins known to recognize carbohydrates. In some embodiments, the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic bond.
[00111] In some embodiments, the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an S-glycosidic bond.
[00112] Aspects of the invention relate to compounds based on galactoside structure with a Selenium bridge [X] to another galactose, hydroxyl cyclohexane, aromatic moiety, alkyl, aryl, amine, or amide.
[00113] As used herein, the term "alkyl group" is meant to comprise from 1 to 12 carbon atoms, for example 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-chain. In some embodiments, the alkyl group may also form a cycle comprising from 3 to 7 carbon atoms, preferably 3, 4, 5, 6, or 7 carbon atoms. Thus alkyl encompasses any of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1- methylcyclopropyl.
[00114] As used herein, the term "alkenyl group" is meant to comprise from 2 to 12, for example 2 to 7 carbon atoms or 3 to 7 carbon atoms. The alkenyl group comprises at least one double bond. In some embodiments, the alkenyl group encompasses any of vinyl, allyl, but-1-enyl, but-2-enyl, 2,2-dimethylethenyl, 2,2- dimethylprop-1 -enyl, pent-1 -enyl, pent-2-enyl, 2,3-dimethyibut-1-enyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, prop-1 , 2-dienyl, 4~methylhex-1-enyl, cycloprop-1 -enyl group, and others. [00115] As used herein, the term "alkoxy group" relates to an alkoxy group containing 1-12 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments the alkoxy group contains 1 to 7 or 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. Thus the term "alkoxy group" encompasses a methoxy group, an ethoxy group, a propoxy group, a isopropoxy group, a n-butoxy group, a sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 3-methylbutoxy group, 2,2-dimethylpropoxy group, n- hexoxy group, 2-methylpentoxy group, 2,2-dimethylbutoxy group 2,3-dimethylbutoxy group, n-heptoxy group, 2-methylhexoxy group, 2,2-dimethylpentoxy group, 2,3- dimethylpentoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and 1-methylcyclopropyloxy group.
[00116] As used herein, the term "aryl group" is meant to comprise from 3 to 12 carbon atoms. Said aryl group may be a phenyl group or a naphthyl group. The above-mentioned groups may naturally be substituted with any other known substituents within the art of organic chemistry. The groups may also be substituted with two or more of the said substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro. Alkyl groups are as defined above containing 1 to 7 carbon atoms. Alkenyl are as defined above containing 2 to 7 carbon atoms, preferably 2 to 4. Alkoxy is as defined below containing 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may contain an unsaturated carbon atom. Combinations of substituents can be present such as trifluoromethyl.
[00117] As used herein, the term "heteroaryl group" is meant to comprise any aryl group comprising from 4 to 18 carbon atoms, wherein at least one atom of the ring is a heteroatom, i.e. not a carbon. In some embodiments, the heteroaryl group may be a pyridine, or an indole group.
[00118] The above-mentioned groups may be substituted with any other known substituents within the art of organic chemistry. The groups may also be substituted with two or more of the substituents. Examples of substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro. Alkyl groups are as defined above containing 1 to 7 carbon atoms. Alkenyl are as defined above containing 2 to 7 carbon atoms, for example 2 to 4. Alkoxy is as defined below containing 1 to 7 carbon atoms, for example 1 to 4 carbon atoms, which may contain an unsaturated carbon atom.
Monomeric-selenium polvhvdroxylated- cycloalkanes
[00119] In some embodiments, the compound is a monomeric-selenium polyhydroxylated- cycloalkanes compound having Formula (1 ) or Formula (2) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0001
Formula 1
Formula 2
Figure imgf000030_0002
wherein X is 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, S02, P02, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherei R2, and R3 are independently selected from the group consisting of CO, 02, S02, P02, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group.
Oligomeric selenium polyhydroxylated and Dimeric selenium polyhydroxylated - cvcloaklanes compounds
[00120] In some embodiments, the compound is a dimeric-polyhydroxylated- cycloalkane compound. In some embodiment, the compound is an oligomeric selenium polyhydroxylated - cycloalkane compound with 3 or more units.
[00121] In some embodiments, the compound has the general formulas (3) and (4) below or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000032_0001
Formula 3
Figure imgf000032_0002
Formula 4
wherein X is 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 acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein n£ 24,
wherei 1
Figure imgf000033_0001
and R2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triaZol-1 -yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, and a substituted imino group
[00122] In some embodiments, n=1. In some embodiments, n=2. In some embodiments, n=3.
[00123] As used herein, the term "alkyl group" relates to an alkyl group containing 1-7 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments the alkyl group contains 1 -4 carbon atoms, which may include one or more unsaturated carbon atoms. The carbon atoms in the alkyl group may form a straight or branched chain. The carbon atoms in said alkyl group may also form a cycle containing 3, 4, 5, 6, or 7 carbon atoms. Thus, the term "alkyl group" used herein encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.
[00124] In some embodiments, the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
[00125] Aspect the present invention relates to a compound of Formula (7) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000035_0001
Formula 7
[00126] In some embodiments, the compound has the general formulas (5) and (6) below or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000035_0003
Figure imgf000035_0002
wherein X is Se, Se-Se, Se-S; S-Se, Se-S02, or S02-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 acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof, wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherei
Figure imgf000036_0001
R2, R3 and R4 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D- galactose, C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group.
[00127] In some embodiments, the halogen is a fluoro, a chloro, a bromo or an iodo group.
[00128] In some embodiments, the compound has the following formulas as shown in Table 1 and is an inhibitor of galectln-3.
[00129] Table 1 shows non-limiting examples of monomeric Se Galactosides.
Table 1
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
[00130] In some embodiments, the compound has the following formulas as shown in Table 2 and is an inhibitor of galectin-3.
[00131] Table 2 shows non-limiting examples of Di-Se saccharides.
Table 2
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
[00132] In some embodiments, the compound has the following formulas shown in Table 3 and is an inhibitor of ga!ectin-3
[00133] Table 3 shows non-limiting examples of oligo-Se saccharides.
Table 3
Figure imgf000046_0001
Figure imgf000047_0001
[00134] Tetrameric Se-galactosides are expected to have higher affinity to the CRD versus the trimeric structure due to additional potential interaction of hydroxyl groups with amino-acids in the CRD vicinity (see Example 14).
[00135] Without being bound to the theory, the galactose-selenium compounds described herein have an enhanced stability as its structure is less prone to hydrolysis (metabolism) and oxidation, e.g. aromatic ring without substitutions, Carbon-Oxygen systems, Carbone-Nitrogen system etc.
Computational scoring of ligand-protein affinity
[00136] Standard assays to evaluate the binding ability of the ligand toward target molecules are known in the art, including for example, ELISAs, western blots and RIAs. Suitable assays are described in detail herein. In some embodiments, the 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 effects of the compounds on functional properties of the galectin are described in further detail herein.
[00137] One way to determine protein-ligand binding affinity uses a structure- based model that can predict the interaction of the protein -ligand complex that results when the ligand binds to the protein. Such structures may be studied by x-ray crystallography. In some embodiments, compounds of interest can be screened“in silico” to predict the ligand’s affinity to the lectin or galectin proteins using any scoring system known in the art.
[00138] in some embodiments, a computational modeling can be used to facilitate structure-based drug design. The in-sllico model also enables to visually inspect the protein-compound interaction, conformational strain and possible steric clashes and avoid them. In some embodiments, the protein-ligand affinity can be scored using a Glide (Schrodinger, Portland OR). The combination of position and orientation of a ligand relative to the protein, along with the flexible docking, is referred to as a ligand pose and scoring of the ligand pose for Glide is done with GlideScore. GlideScore is a quantitative measurement that provides an estimate for a ligand binding free energy. It has many terms, including force field (electrostatic, van der Waals, etc...) contributions and terms rewarding or penalizing interactions known to influence ligand binding. It contains two energetic elements; the enthalpic and entropic contributions of a biological reaction. The thermodynamic rationale for enthalpy-entropy compensation is based on the fact that, as the binding becomes stronger, enthalpy becomes more negative and entropy concomitantly tends to decrease due the formation of a tight complex. As such, ligands having the lowest GlideScore can be selected.
[00139] The methods and compounds are provided for the inhibition of Galectin-3 and/or Galectin-1 , however the in-silico model, assays and compounds described herein may be applied to other galectin proteins and lectins.
[00140] An in-silico model of Galectin-3 CRD based on the 1 KJR crystal structure of human Galectin-3 CRD (Sorme, P. et al. (2005) J.Am.Chem.Soc. 127: 1737-1743) and improved using Galectin-3 known "actives" and "inactive" compounds as a training and test sets was used. The 1 KJR crystal structure was selected due to its unique extended cavity that allows for larger substitutes (e.g. indole or naphtalen) on the C3 position of the galactose (Vargas-Berebgurl 2013, Barondes 1998, Sorme 2003). Table 4 shows the GlideScore for the different di- galactosides: (1 ) thiogalactoside, galactoside, selenogalactoside, diselenogalactoside having identical substituents.
Table 4
Figure imgf000048_0001
Figure imgf000049_0001
[00141] The GlideScore data showed that the introduction of Se to the anomeric carbon (G-625) on the galactose scores the same as the thiogalactoside (TD-139, also referred as G-240). The results also showed that the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) have comparable overall estimated predictor of free energy. As such, the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) are expected to have comparable affinity to galectin-3 and inhibitor effects.
[00142] These compounds were tested for their affinity with integrins and with galectin-3. Surprisingly, the selenogalactoside compound (G-625) showed from about at least 2 to about at least 3 times better affinity to galectin-3 and to integrins.
[00143] The Se atom allows the rest of the molecule (for example G-625) to fulfill the interactions seen with TD-139, but with a superior affinity to Galectin-3 vs. TD-139 as was shown in the Elisa based assay and fluorescent polarization assay. In some embodiments, the selenogalactoside of Formula (1 ) has an affinity to galectin-3 that is at least twice or at least three time stronger than TD-139. In some embodiments, the selenogalactosides of the present invention have an affinity to galectin-3 that is at least twice or at least three times stronger than the corresponding thiogalactoside.
[00144] The 'drugability' characteristic, as defined by the computational structure analysis considers compounds: (1 ) stereoisomerization, (2) position of the hydroxyl groups on the sugar (e.g. axial or equatorial) and (3) position and nature of substituents.
[00145] 1 ) Stereoisomerization: It should be noted that compounds with identical 2D nomenclature can have a different 3D structure that can lead to a very different binding pose as well as different predicting binding free energy predictor,
GLideScore.
[00146] 2) Hydroxyl groups: The position of the hydroxyl groups on the sugar
(e.g. axial or equatorial) play an important role in compounds binding. Specifically, the present invention relates to compounds that are galactose-based bound to a Selenium atom bound to the anomeric carbon, serving as a linker to the rest of the molecule.
[00147] 3) Substituents: According to some aspects, the compounds can have substituents capable of, or designed to, reach amino acids that are part of the binding site which were known and unknown to play a role in ligand's binding. One of skill in the art would appreciate that galectins bind the monosaccharide galactose with dissociation constants in the millimolar range. It has been shown that addition of N-acetyl glucosamine to galactose can provide additional interaction with neighboring sites boosts the compound affinity to galectin-3 over 10 fold (Bachhawat-Sikder Et al. FEBS Lett. 2001 Jun 29;500(1-2):75-9).
[00148] Further addition of non-natural derivatives, such as naphtol, at the 3 position of saccharides, can enhance the affinity to the low micromolar range, e.g. 0.003 mM. This substitution exploits cation-p interactions with the surface residue Arg 144.
[00149] Human Galectin-3 cavity is shallow with high solvent accessibility. It is very hydrophilic but capable of forming cation-p interactions with Arg144 and possibly Trp181 (Magnani 2009, Logan 201 1 ). It has been shown that upon ligand's binding, Arg144 moves 3.5A upwards from the protein surface to make a pocket for the Arene-Arginine interaction. It should be noted that Arg144 is absent in other galectin, e.g. Gal-1 , Gal-9 and this is being exploited in our in-silico model. Similarly, potency can be improved by exploiting cation-p interactions with the surface residue of Arg186. For example, triazole substitution at C3 of galactose has been reported to increase Galectin 3 affinity (Salameh BA et al. Bioorg. Med. Chem. Lett. 2005 Jul 15; 15(14):3344-6.)
[00150] Tryptophan 181 at subsite C is conserved throughout the galectin family. A p - p stacking interaction between the Trp181 (W181 ) side chain and a carbohydrate residue (galactose being the natural carbohydrate occupant) accommodated within subsite C occurs in all reported galectin-saccharide complexes.
[00151] To develop effective approaches for the structure-based design of potent galectin inhibitors, such as galectin-3 inhibitors, it is important to understand the detailed molecular basis for carbohydrate recognition, based on the three dimensional structure and physiochemical properties of the conserved binding motif. High-resolution structural information greatly aids in this respect (see Ultra-High- Resolution Structures and Water Dynamics, Saraboji, K. et al., Biochemistry. 2012 Jan 10; 51 (1 ): 296-306.). While it is clear that the galectin-3 CRD site is pre- organized to recognize a carbohydrate like framework of oxygens (see FIG. 2), it was not expected to recognize Se containing compounds with a two-fold to a three- fold increased activity.
[00152] In GaLectin-3 (See CRD amino-acids in vicinity of the binding pocket in FIG. 3), the side chain of Arg144 is capable of adopting different conformations due to its inherent flexibility that could contribute to greater affinity via an arginine-arene interaction (a cation- p or tt - p stacking interaction) with the aromatic moiety.
[00153] In some embodiments, galectin’s key residues that affect ligand affinity were identified using computational alanine scanning mutagenesis (ASM) or an“in- silico-alanine-scan”. ASM can be performed by sequential replacement of individual residues by alanine to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of an individual amino acid to the functionality of the protein.
[00154] To better understand the importance of residues within the CRD binding pocket (FIG. 3) an“in-silico-alanine-scan” was run by docking in Glide the compound of Formula 1 and a galectin-3 inhibitor, 3,3'-Dideoxy-3,3'-di-[4-(3- fluorophenyl)-IH-i,2,3-triazol-l-yi]-l,l'-sulfanediyl-di-D-galactopyranoside (TD139, see W0201600531 1A1 , incorporated by reference in its entirety). Residues that were predicted to be involved in the binding were mutated and it was expected that the mutations to alanine would have an effect on the GlideScore results. The Alanine Scan was used to predict the importance of residues to the ligand's binding.
[00155] For example, it was reported that Galectin-3 R186S abolishes carbohydrate interactions. The R186S was shown to have has a selectively lost affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, and has lost the ability to activate neutrophil leukocytes and intracellular targeting into vesicles (see Salomonsson E. et al. , J Biol Chem. 2010 Nov 5;285(45):35079- 91.)
[00156] Table 5 shows the in-silico Alanine scan comparison results using TD- 139 Compound
Table 5
Figure imgf000052_0001
[00157] Table 6 shows the in-silico Alanine scan comparison results using G- 625 Compound having Formula 1
Table 6
Figure imgf000052_0002
Figure imgf000053_0001
** dG>100 suggests increase in ligand binding upon mutation to Alanine while dG<100 suggests decrease in ligand binding upon mutation.
[00158] These results suggest that the 'molecular interaction profile' of TD-139 differs from that of G-625. Tables 5 and 6 show the interaction profile as predicted by the in-silico model. TD139 is greatly affected by the introduction of R186A mutation (there is "-15% reduction” in the GlideScore which is a predictor for the free binding energy). On the other hand, R186A has less of an effect on G-625 and G- 625 is more sensitive to H158A mutation.
[00159] Surprisingly, the Alanine scan showed that residue N174 play an important role in the binding of both TD-139 and G-625 compounds. Without being bound to the theory it is possible that residue N174 may help in positioning the Galactose core in 'the optimal orientation’ that will enable the CRD site to recognize carbohydrate like framework of the oxygens.
[00160] The in-silco Alanine scan suggested that G-625 has a unique binding profile while maintaining the interactions with known CRD residues like Arg 162, Arg 186 and Arg 144. Based on these results the interactions with residues located at Site A: S237; Site B: D148; Site C-D: A146, K176, G182 and E165; and N166 in Site C-loop (FIGS. 2 and 3) were explored to improve the interaction with the CRD.
Synthetic route
[00161] The compounds of this invention may be prepared by the following general methods and procedures. It should be appreciated that where typical or preferred process conditions (e.g. reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants, solvents used and pH etc., but such conditions can be determined by one skilled in the art by routine optimization procedures.
[00162] In some embodiments, the compound was synthetized using the synthetic route shown in FIG. 4
[00163] For example, compound G-625 was prepared as detailed in Example 10.
Pharmaceutical compositions
[00164] Aspects of the invention relate to the use of the compounds described herein for the manufacture of medicaments. Some embodiments relate to the compounds or the use of the compounds having formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof. Some embodiments relate to the compounds or the use of the compounds of Tables 1-4.
[00165] Aspects of the invention relate to pharmaceutical compositions comprising one or more of the compounds described herein. In some embodiments, the pharmaceutical compositions comprise one or more of the following: pharmaceutically acceptable adjuvant, diluent, excipient, and carrier.
[00166] The term “pharmaceutically acceptable carrier” refers to a carrier or adjuvant that may be administered to a subject (e.g., a patient), together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount or an effective mount of the compound.
[00167] "Pharmaceutically acceptable carrier" refers to 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 can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
[00168] Some aspects of the present invention relate to a pharmaceutical composition comprising the compound of the invention and optionally a pharmaceutically acceptable additive, such as carrier or excipient. In some embodiments, the pharmaceutical composition comprising the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient. In some embodiments, the pharmaceutical composition comprising the compound of Tables 1-4 or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
[00169] In some embodiments, the pharmaceutical composition comprises a compound described herein as active ingredient together with a pharmaceutically acceptable adjuvant, diluent, excipient or carrier. A pharmaceutical composition can comprise from 1 to 99 weight % of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier and from 1 to 99 weight % of a compound described herein.
[00170] The adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention are pharmaceutically acceptable, i.e. are compatible with the compounds and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person within the art.
[00171] An effective oral dose of the compound of the present invention to an experimental animal or human may be formulated with a variety of excipients and additives that enhance the absorption of the compound via the stomach and small intestine.
[00172] The pharmaceutical composition of the present invention may comprise two or more compounds of the present invention. The composition may also be used together with other medicaments within the art for the treatment of related disorders.
[00173] In some embodiments, the pharmaceutical composition comprising one or more compounds described herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder, or, for administration via the eye, intra-ocuiariy, intravitreaiiy or corneally.
[00174] in some embodiments, the pharmaceutical composition comprising one or more compounds described herein may be in the form of, for example, tablets, capsules, powders, solutions for injection, solutions for spraying, ointments, transdermal patches or suppositories. [00175] Some aspects of the present invention relate to pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
[00176] An effective oral dose could be 10 times and up to 100 times the amount of the effective parental dose.
[00177] An effective oral dose may be given daily, in one or divided doses or twice, three times weekly, or monthly.
[00178] In some embodiments, the compounds described herein can be co- administered with one or more other therapeutic agents. In certain embodiments, the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention (e.g., sequentially, e.g., on different overlapping schedules with the administration of the compound of the invention. In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time that the compound of the invention. When the compositions include a combination of the compound of this invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
[00179] In some embodiments, a therapeutically effective amount of the compound or of the composition can be compatible and effective in combination with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other pharmaceuticals and nutraceuticals drugs or supplement, or combinations thereof without limitation.
[00180] In some embodiments, the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof. In some embodiments, the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or 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 combinations thereof. In some embodiments, the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1- 4 or a pharmaceutically acceptable salt or solvate thereof is administered with one or more anti diabetic drug. In some embodiments, administration of the compound of the present invention and the active agent produces a synergistic effect. In some embodiments, the active agent is an antidiabetic drug.
[00181] As used herein, the term“synergistic effect” refers to the correlated action of two or more agents of the present invention so that the combined action is greater than the sum of each acting separately. In some embodiments, the compounds of the present invention and the active agent can be administered simultaneously or sequentially.
[00182] Aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
[00183] Aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other anti neoplastic agents of multiple mechanisms.
Methods of treatment
[00184] Some aspects of the invention relate to the use of the compounds described herein or the composition described herein for use in the treatment of a disorder relating to the binding of a galectin to a ligand. In some embodiments, galectin is gaiectin-3
[QG18S] Some aspects of the invention relate to the method of treating various disorders relating to the binding of a galectin to a ligand. In some embodiments, the methods comprise administering in 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 ga!ectin-3. Levels of galectin, for example gaiectin-3 can be quantified using any methods known in the art. [00186] Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFbl -Receptor) so as to recover normal regenerative activity in tissues.
[00187] Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
[00188] Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a Galectin, such as Galectin-3 binding to an Insulin-Receptor or TGFbl -receptor in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1-4 or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
[00189] Aspects of the invention relate to compounds, compositions and methods of treating various disorders in which lectin proteins play a role in the pathogenesis, including but not limited to treating systemic insulin resistance. In some embodiments, the compound can reverse galectin-3 binding to the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
[00190] Aspects of the invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance. In some embodiments, the systemic insulin resistance is associated with obesity where elevated galectin-3 interacts with insulin receptor. In some embodiments, treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
[00191] Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes. Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM). Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores sensitivity of cells to insulin activity. In some embodiments, the compound inhibits galectin-3 interaction with Insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanism. Aspects of the invention relate to compounds, compositions and methods for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD. Aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance, and the compensatory hyperinsulinemia which affects some 65-70% of women with PCOS. Aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TOFβ Receptor pathway in kidney chronic disease in some embodiments, the compound can inhibit the overexpression of TGFb receptor signaling system triggered by Insulin resistance in diabetic and cause decline in renal function, and can reverse the established lesions of diabetic glomerulopathy.
[00192] In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof. In some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof. In some embodiments, the compound is administered with one or more anti diabetic drug. In some embodiments, administration of the compound of the present invention and the active agent produces a synergistic effect.
[00193] Aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor. In some embodiments, treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
[00194] In some embodiments, the compounds or compositions of the invention that bind to insulin receptor (also identified as IR, INSR, CD220, HHF5). [00195] Aspects of the invention relate to compounds, compositions and methods of treating diseases caused by disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ).
[00196] In some embodiments, the disorder is an inflammatory disorder, for example inflammatory bowel disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
[00197] in some embodiments, the disorder is fibrosis, for example liver fibrosis, pulmonary fibrosis, kidney fibrosis, heart fibrosis or fibrosis of any organ compromising the normal function of the organ.
[00198] In some embodiments, the disorder is cancer.
[00199] in some embodiments, the disorder is an autoimmune disease such as rheumatoid arthritis and multiple sclerosis.
[00200] in some embodiments, the disorder is heart disease or heart failure.
[00201] in some embodiments, the disorder is a metabolic disorder, for example diabetes.
[00202] In some embodiments, the disorder relating is pathological angiogenesis, such as ocular angiogenesis, disease or conditions associated with ocular angiogenesis and cancer.
[00203] In some embodiments, the composition or the compound can be used in the treatment of nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic conditions or cancers.
[00204] In some embodiments, the composition can be used in the treatment of liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis.
[00205] In some embodiments, the composition or the compound is capable of enhancing anti-fibrosis activity in organs, including but not limited to, liver, kidney, lung, and heart.
[00206] In some embodiments, the composition or the compound can be used in treatment of inflammatory disorders of the vasculature including atherosclerosis and pulmonary hypertension.
[00207] In some embodiments, the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy. [00208] In some embodiments, the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
[00209] In some embodiments, the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
[00210] Aspects of the invention relates to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.
[00211] Aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
[00212] Aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH). In other aspects, the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
[00213] Aspects of the invention relates to a composition or a compound used in treating or a method of treating inflammatory and autoimmune disorders in which galectins are at least in part involved in the pathogenesis including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
[00214] Aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins. In some embodiments, the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins. In some embodiments, the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the composition or a compound can be used to treat primary and secondary cancers. [00215] In some embodiments, the compound is a monomeric-selenium polyhydroxylated- cycloalkanes compound or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000062_0001
Wherein X is Selenium;
Wherein Z is a carbohydrate or linkage consisting of O, S, C, NH, CH2, Se, amino acid to R2 and R3;
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 acid, and a combination thereof.
Wherein R1, R2, and R3 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50-200 D.
[00216] In some embodiments, the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D- galactose, C3-[1 ,2,3]-triaZol-1 -yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group
[00217] In some embodiments, the compound is a dimeric-polyhydroxylated- cycloalkane compound.
[00218] In some embodiments, the compound has the general or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000064_0001
Wherein X is Se, Se-Se or Se-S;
Wherein Z is independently selected from a carbohydrate (composing, for example, an oligomeric Se-galactoside) or linkage consisting of O, S, C, NH, CH2, Se, and amino acid to R3 and R4;
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 amino acid;
Wherein R1, R2, R3, and R4 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, Hydrogen, and hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50- 200 D.
[00219] In some embodiments, the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted With at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D- galactose, C3-[1 ,2,3]-triaZol-1 -yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group.
[00220] Aspect the present invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000065_0001
Wherein n£ 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 amino acid;
Wherein and R2 are independently selected from the group consisting of CO, SO2, SO, PO2, PO, CH, Hydrogen, hydrophobic linear and cyclic hydrocarbon including heterocyclic substitutions of molecular weight of 50-200 D including, but not limited to:
a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens;
b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group,
c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group; and
d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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,
e) a saccharide; a substituted saccharide; D-galactose; substituted D-galactose; C3- [1 ,2,3]-triaZol-1 -yl-substituted D-galactose; hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group.
EXAMPLES
Example 1 : Compound inhibition of Galectin binding to labeled probes
[00221] Fluorescein-labeled probes have been developed which bind to Galectin 3 and other Galectin proteins and these probes have been used to establish assays (FIGS. 5A & 5B) that measure the binding affinity of ligands for the Galectin proteins using Fluorescence Polarization (Sorme P, et al. Anal Biochem. 2004 Nov 1 ;334(1 ):36-47).
[00222] Compounds described herein avidly bind to Galectin-3, as well as other Galectin proteins, using this assay format (FIG. 5A) and displace the Fluorescein- labeled probe with high affinity, with IC50’s (concentration at 50% inhibition) of between about 5 hM to about 40 mM. In some embodiments, the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 pM. In some embodiments, the IC50 is from about 0.5 mM to about 10 mM. In some embodiments, the IC50 is from about 5 mM to about 40 mM.
[00223] Compounds claimed under this invention were synthesized (see Table 1 , 2, 3 & FIG. 4) and tested for binding to the CRD in the Fluorescent polarization assay (FIG. 5A) and showed an inhibitory activity (FIG. 7).
[00224] G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-
1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3-fluorophenyl)-1 H-
1 ,2,3-triazol-1-yl)-1-seleno-. G-625 has single selenide bridge between two Aryl- triazole-galactosides, (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
[00225] G-626 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-
1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3-fluorophenyl)-1 H-
1 ,2,3-triazol-1-yl)-1-seleno-. G-625 has double selenide bridge between two Aryl- triazole-galactosides (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
[00226] G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
Example 2: Compound inhibition of Galectin binding using FRET assay
[00227] FRET assay (fluorescent resonance energy transfer) assays were developed for evaluating the interaction of Galectin proteins, including but not limited to Galectin-3, with a model fluorescent-labeled probe (see FIG. 5B). Using this assay, compounds described herein avidly bind to Galectin-3, as well as other Galectin proteins, using this assay and displace the probe with high affinity, with IC50’s (concentration at 50% inhibition) of between about 5 hM to about 40 mM. In some embodiments, the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 mM. In some embodiments, the IC50 is from about 0.5 mM to about 10 mM. In some embodiments, the IC50 is from about 5 mM to about 40 mM. Example 3: Compound inhibition of qalectin binding to physiologic ligands
[00228] High levels of serum Galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is an enduring disease which can be resolved but can be prevented by taking care. It is one of the commonly found metabolic syndromes everywhere in the world. Diabetes mellitus mainly associates with central nervous system and peripheral nervous system which are chronic complications. Diabetes mellitus is a commonly seen metabolic syndrome of diabetes where the body cannot use glucose and stores in blood which may damage kidneys, nerves, heart, eyes, and other complications.
[00229] Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS), Mets is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
[00230] Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. I. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
[00231] Recent studies also indicate that Galectin-3 plasma levels are significantly elevated in human and animal obesity models,
[00232] In obesity, macrophages and other immune cells have been reported to recruited to insulin target tissues, and promoting a chronic inflammatory state and insulin resistance. Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decreased in insulin sensitivity. Inhibition of Galectin-3 could be a new drug target to treat insulin resistance.
[00233] Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that control cell growth and differentiation. Insulin receptor substrate (IRS) is the common intermediate, which include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiate signal transduction. However, when serine 307 is phosphorylated, signaling is diminished. Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
[00234] Compounds claimed under this invention were synthesized (see Table 1 , 2, 3 and 4) and tested for inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 6B).
[00235] For example, G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1-yl)-1-seleno-. G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
[00236] G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
[00237] Compounds claimed under this invention were synthesized (see Table 1 , 2, 3 and 4) and tested for inhibitory activity against TGF-b-I Receptor - galectin-3 interaction. This interaction of TGF-b receptor with galectin-3 is important pathological step in many inflammatory and fibrosis pathways. We have shown that the compounds described herein were inhibitors of this interaction (FIG. 9).
[00238] For example, G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazoM -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1-yl)-1-seleno-. G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the TGF-b receptor - galectin-3 (FIG. 9).
[00239] G-662 a seleno-monosaccharide was synthesized (see Table 1 ), showed an inhibitory activity in the TGF-b receptor - galectin-3 interaction (FIG. 9). Example 4: Compound binding to amino acid residues in qalectin proteins
[00240] Heteronuclear NMR spectroscopy is used to evaluate the interaction of compounds described herein with galectin molecules, including but not limited to galectin-3, to assess the interaction residues on the galectin-3 molecule.
[00241] Uniformly 15N-labeled Gal-3 is expressed in BL21 (DE3) competent cells (Novagen), grown in minimal media, purified over a lactose affinity column, and fractionated on a gel filtration column, as described previously for production of Gal-1 (Nesmelova IV, Pang M, Baum LG, Mayo KH. 1 H, 13C, and 15N backbone and side- chain chemical shift assignments for the 29 kDa human galectin-1 protein dimer. Biomol NMR Assign 2008 Dec;2(2):203-205).
[00242] Uniformly 15N-labeled Gal-3 is dissolved at a concentration of 2 mg/ml in 20 mM potassium phosphate buffer at pH 7.0, made up using a 95% H2O/ 5% D2O mixture. 1H-15N HSQC NMR experiments are used to investigate binding of a series of compounds described herein. 1 H and 15N resonance assignments for recombinant human Gal-3 were previously reported (Ippel H, et al. (1 )H, (13)C, and (15)N backbone and side-chain chemical shift assignments for the 36 proline-containing, full length 29 kDa human chimera-type galectin-3. Biomol NMR Assign 2015 Apr;9(1 ):59-63.).
[00243] NMR experiments are carried out at 30°C on Bruker 600 MHz, 700 MHz or 850 MHz spectrometers equipped with H/C/N triple-resonance probes and x/y/z triple-axis pulse field gradient units. A gradient sensitivity-enhanced version of two-dimensional 1H-15N HSQC is applied with 256 (t1 ) x 2048 (t2) complex data points in nitrogen and proton dimensions, respectively. Raw data are converted and processed by using NMRPipe and were analyzed by using NMRview.
[00244] These experiments show differences between compounds described herein in the binding residues in the carbohydrate binding domain of galectin-3.
Example 5: Cellular activity of cytokine activity related to qalectin binding inhibition
[0024S] Example 1 describes the ability of compounds of this application to inhibit the binding of physiologic ligands to galectin molecules. In the experiments of this example, the functional implications of those binding interactions were evaluated. [00246] One of the interactions with galectin-3 that is inhibited by the compounds described herein was TGF-b receptor. Therefore, experiments were done to evaluate the effect of compounds on TGR-b receptor activity in cell lines. Various TGF-b responsive cell lines, including but not limited to LX-2 and THP-1 cells, were treated with TGF-b and response of the cells was measured by looking at activation of second messenger systems, including but not limited to phosphorylation of various intracellular SMAD proteins. After establishing that TGF-b activates the second messenger systems in the various cell lines, the cells were treated with compounds described herein. These experiments showed that these compounds inhibit TGF-b signaling pathways, confirming that the binding interaction inhibition described in Example 1 has a physiological role in cellular models.
[00247] Cellular assays were also performed to evaluate the physiological significance of inhibiting the interaction of galectin-3 with various integrin molecules. Cell-cell interaction studies were performed using monocytes binding to vascular endothelial cells, as well as other cell lines. Treatment of cells with compounds described herein was found to inhibit these integrin-dependent interactions, confirming that the binding interaction inhibition described in Example 1 had a physiological role in cellular models.
Bioassay Procedures:
[00248] Procedure for MCF-7 Cells (colon cancer) was as follow:
1. MCF-7 cells were resuspended in culture media containing 4X Pen/Strep and 0.25% Fetal Bovine Serum (Gibco lot# 1202161 ).
2. 100 ul media was added with approximately 4,000-10,000 cells/well, passage # 5 up to 30) and cells were incubated for at least 24 hrs at 37°C.
3. Tested compound was diluted serially in assay media as above, usually at a range of 100 mg/ml to 20 ng/mL
4. 100ml serial diluted compound was added in duplicate to cells in assay plate.
Final volume of each well was 200ml, (containing 2x Pen/Strep, 0.25% FBS and compound as indicated
5. Cells were incubated 60-80 hours at 37°C.
6. 20ml of Promega Substrate [CellTiter 96 Aqueous One Solution] Reagent was added to each well. 7. Cells were incubated 37°C for 4-8 hrs and read OD at 490 nm.
[00249] Procedure for HTB-38 Cells (Breast cancer) was as follow:
1. HTB-38 cells were resuspended in culture media containing 8 ng/ml h-IFN- gamma, 4X Pen/Strep and 10% Fetal Bovine Serum (Gibco lot# 1260930).
2. Cells were transferred at 10OmI/well in assay plate (4,000-10,000 cells/well, passage# 4-30).
3. Tested compound was diluted serially in assay media as above, usually in range of 100 mg/ml to 20 ng/mL
4. 10OmI/well serial diluted compound was added in duplicate to cells. Final volume of each well was 200mI, containing 4 ng/ml h-IFN-gamma, 2x Pen/Strep,
5. Cells were Incubate 60-90 hours at 37°C.
6. 20mI of Promega Substrate [CellTiter 96 Aqueous One Solution] Reagent was added to each well.
7. Cells were incubated at 37°C for 4-8 hrs and read OD at 490 nm.
[00250] Cellular motility assays are performed to evaluate the physiological significance of inhibiting the interaction of galectin-3 with various integrin and other cell surface molecules defined in Example 1. Cellular studies are performed using multiple cell lines in a semi-permeable membrane separated well apparatus. Treatment of cells with compounds described herein is found to inhibit cellular motility, confirming that the binding interaction inhibition described in Example 1 has a physiological role in cellular models.
Example 6: In-vitro Inflammatory Model fa monocyte based assay)
[00251] A model of macrophage polarization was set up, starting from THP-1 monocytes culture which is differentiated into inflammatory macrophages using PMA (Phorbol 12-myristate 13-acetate) for 2-4 days. Once differentiated (M0 macrophages), the macrophages were induced with LPS or LPS and IFN-gamma for macrophage activation (M1 ) to inflammatory stage for 1 -3 days. Array of cytokines and chemokines were analyzed to confirm the polarization of THP-1 -derived macrophages to inflammatory stage. The impact of the anti-galectin 3 compounds on macrophage polarization was assessed first by monitoring cell viability using a colorimetric method (using a tetrazolium reagent) to determine the number of viable cells in proliferation or cytotoxicity assays (Promega, The CellTiter 96® AQueous One Solution Cell Proliferation Assay which contains a novel tetrazolium compound [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES)) and inflammatory stage evaluated by a quantitatively measure of the chemokine Monocyte Chemoattractant Protein-1 (MCP-1 / CCL2), a key protein that regulates migration and infiltration of monocytes/macrophages in cellular process of inflammation. Follow-up testing for the expression and secretion of other cytokines and chemokines were done for leading active compounds.
[00252] THP-1 cells were stimulated by microbial endotoxin which transforms the cells to inflammatory macrophages (M1 ) which secret inflammatory cytokines like Monocyte Chemoattractant Protein-1 (MCP-1 ).
[00253] In this Example the method steps were as followed:
1 ) THP-1 cells were cultured in media containing Gentamicin
2) THP-1 cells are transfer to wells in a 96 well plate 2,000 cells/well for 2 days incubation in assay media containing 10 ng/ml PMA
3) Serial dilution of test compounds is made in LPS (10 ng/ml) containing media
4) To each well 100 ml of compounds / LPS solution is added to a final assay volume of each well of 200 ml which contains also Gentamicin and 5 ng/ml PMA
5) Cells are incubated up to 8 days.
6) Every other day samples of 60 ul are removed for bio-assay
7) At termination 15 ml of Promega Substrate CellTiter 96 Aqueous One Solution is added to each well to monitor cytotoxicity (at 490 nm)
8) For cellular biomarkers evaluation the cells are washed 1XPBS and extracted with 200ul of Lysis buffer for 1 hour. Extract is spanned down 10 minutes and 120ul sample is removed from top. All samples are kept at -70C until testing.
Example 7: Evaluation of compound absorption, distribution, metabolism, and elimination
[00254] Compounds described herein are evaluated for physicochemical properties, including but not limited to solubility (Thermodynamic and Kinetic method), various pH changes, solubility in biorelevant medium (FaSSIF, FaSSGF, FeSSIF), Log D (Octanol/water and Cyclohexane/water), chemical stability in plasma, and blood partitioning.
[00255] Compounds described herein are evaluated for in vitro permeability properties, including but not limited to PAMPA (parallel artificial membrane permeability assay), Caco-2, and MDCK (wild type)
[00256] Compounds described herein are evaluated for animal pharmacokinetic properties, including but not limited to pharmacokinetics by various routes viz., oral, intravenous, intraperitoneal, subcutaneous in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (New Zealand white), dogs (Beagle), Cynomolgus monkeys, etc., tissue distribution, brain to plasma ratio, biliary excretion, and mass balance.
[00257] Compounds described herein are evaluated for protein binding, including but not limited to plasma protein binding (ultra-Filtration and Equilibrium Dialysis) and microsomal protein binding.
[00258] 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 microsome metabolism, S-9 fraction metabolism, effect on cryopreserved hepatocyte, plasma stability, and GSH trapping.
[00259] Compounds described herein are evaluated for metabolite identification, including but not limited to identification in vitro (microsomes, S9 and hepatocytes) and in vivo samples.
Example 8: Affinity of the oligomeric Se-qalactosides
[00260] The affinity of the tetrameric se-galactoside and trimeric Se-galactoside of Table 3 were assayed using the fluorescent polarization assay. Tetrameric Se- galactoside is expected to have higher affinity to the CRD versus the trimeric structure due to additional potential interaction of hydroxyl groups with aminoacids in the CRD vicinity.
Example 9: Cell culture adipocyte model
[00261] Cell Culture and Insulin Resistance model used 3T3-L1 fibroblasts that were cultured in DMEM containing 10% FCS and GlutaMAX and differentiated to adipocytes as previously reported (Shewan, A. M., van Dam, E. M., Martin, S., Luen, T. B., Hong, W., Bryant, N. J., and James, D. E. (2003)“GLUT4 recycles via a trans- Golgi network (TGN) subdomain enriched in Syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif”. Mol. Biol. Cell 14, 973-986). Various Insulin resistance models were used. 3T3-L1 adipocytes were cultured with various doses of insulin (10 nM to 100 nM) to cause chronic insulin exposure or 0.1 M to 1 M dexamethasone (DEX) for 8 to 24h at 37 °C or with 1 to 20 ng/ml TNF at 37 °C for 48 h in full DMEM medium. The medium was replaced twice a day with fresh medium containing TNF. After insulin resistance treatment, cells were washed and then serum starved for 1-2 h prior to insulin stimulation and assessment of insulin- regulated kinases and processes. It has been previously shown that this protocol is adequate to return the 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 major nodes of insulin resistance. Cell Metab. 7, 421-433)
[00262] Experiments were performed with 3T3-L1 fibroblasts differentiated to adipocytes cultures following the Promega protocol:
1. On Day 1 , 1 ml vial of low passage number 3T3L1 cells was thawed and combined with 9ml of Maintenance Medium (MM). The cells were centrifuged at 200 x g for 10 minutes and the liquid medium was aspirated.
2. The cell pellet was resuspended in 1 1 ml of MM. The cells were plated at 20,000 cells per 10OmI in a 96-well plate.
3. The cells were grown to confluency at 37°C in 5% C02 with medium replacement every 2 days. Because of the weak adherence of these cells during differentiation, cells were plated on collagen coated plates (Corning, Cat.# 356650). Medium removal and addition was performed at the slowest pipetting speeds possible.
4. On Day 5, the medium was replaced with 10OmI Differentiation Medium I (DM-I) and continued to be replaces every 2 days.
5. On Day 12, the medium was replaced with 10OmI Differentiation Medium II (DM-II).
6. On Day 14, the medium was replaced with 10OmI of MM. the medium was continued to be replaced every 2 days. 7. Insulin responses were measured between 8-11 days.
[00263] 3T3L1 adipocytes were assayed as follows:
1. The medium was replaced with 100mI MM without serum one day before the assay,
2. On the day of the assay, the medium was replaced with 100mI DMEM without serum or glucose (Life Technologies, Cat. # 11966) containing a range of insulin concentrations. The cells were incubated for 1 hour at 37eC in 5% CO2.
3. The medium was removed and 50mI of 2DG (1 mM) in PBS were added and cells were incubated for 10 minutes at 25°C.
4. 25mI of Stop Buffer was added and the sample was briefly shaken.
5. 25mI of Neutralization Buffer was added and the sample was briefly shaken.
6. 100mI of 2DG6P Detection Reagent was added, the sample was briefly shaken and incubate for 1 hour at 25°C.
[00264] Luminescence was recorded with 0.3-1 second integration on a luminometer to evaluate the cellular effect of Galectin-3 on glucose uptake.
[00265] Differentiation of adipocytes cells was monitored by various well- defined insulin related activation markers, including expression of Insulin Receptor (IR) and its activation by insulin, but not limited to IR kinase activity within minutes of exposing to insulin. Inhibition of this insulin activation by treatment with Galectin-3. The effect of Galectin-3 on IR was monitored also by rate of glucose uptake.
[00266] The compounds described herein were found to inhibit the effect of
Galectin-3 and reversal of insulin resistance and recovering of glucose uptake confirming a physiological and potential therapeutic role in systemic insulin resistance in diabetes linked to obesity.
Example 10: G-62S Synthesis procedure
[0026h The G-625 compound was synthesized using the following scheme
(see FIG. 4)
Step-1 :
Figure imgf000078_0001
[00268] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-azido-6-((4- methylbenzoyl)selanyl) 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 , 1.6 g, 4.06 mmol) and potassium 4-methylbenzoselenoate (2, 2.41 g, 10.14 mmol) in EtOAc (30 mL), tefra-n-butyl ammonium hydrogen sulphate (2.75 g, 8.12 mmol) and aq. Na2CO3 (16 mL, 16 mmol) were added sequentially at room temperature (rt) and the reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (Na2S04), filtered and concentrated in vacuo and the residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 0 to 30% EtOAc in hexane] to afford the title compound (3) as a white solid (1.38 g, 66%).
[00269] 1H-NMR (400 MHz; CDCI3): d 2.04 (s, 3H), 2.06 (s, 3H), 2.18 (s, 3H), 2.45 (s, 3H), 2.76 - 2.80 (m, 1 H), 4.03 - 4.17 (m, 3H), 5.44 - 5.53 (m, 3H), 7.27 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H).
Figure imgf000078_0002
[00270] (2S,2’S,ZR,Z’R,4S,4’S,5R,5’R,6R,6’R)-se\enobis(6-(acetoxymethy\)-
4-azido tetrahydro-2H-pyran-2,3,5-triyl) tetraacetate (5): A solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-azido-6-((4-methyl benzoyl)selanyl) tetrahydro-2H-pyran-3,5-diyl diacetate (3, 100 mg, 0.19 mmol) in DMF (4 mL) was degassed with argon for 20 min. The mixture was cooled to -15 °C and Cs2CO3 (127 mg, 0.79 mmol), dimethylamine (2M in THF) (0.39 mL, 0.78 mmol) and a solution of (2R,3R,4S,5R)-2-(acetoxymethyl)-4-azido-6-bromotetrahydro-2H-pyran-3,5-diyl diacetate (307 mg, 0.78 mmol) in DMF (2 mL) were added and again degassed with argon for 20 min. The reaction mixture was stirred at same temperature for 5 min. After checking TLC, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 0% to 50% EtOAc in hexane] to afford the title compound (5) as colorless sticky solid (66 mg, 48%).
[00271] MS: m/z 707 (M+AcOH)+ (ES+)
1H-NMR (crude) (400 MHz; CDCI3): δ 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:
Figure imgf000079_0001
[00272] (2S,2’S,3R,3’R,4S,4’S,5R,5’R,6R,6’R)-selenobis(6-(acetoxymethyl)-
4-(4-(3-fluorophenyl)-1 H- 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, 130 mg 0.183 mmol) and 1-ethynyl-3-fluorobenzene (6, 1 15 mg, 0.918 mmol) in toluene (4 mL), DIPEA (0.07 mL, 0.366 mmol) and Cul (34 mg, 0.183 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a pad of celite bed, washed with EtOAc, dried (Na2S04) and concentrated in vacuo and the residue was washed with Et2O (10 mL) to afford the title compound (7) as a white solid (164 mg, 94%).
[00273] MS: m/z 949 (M+H)+ (ES+)
[Q0274] 1H-NMR (400 MHz; DMSO-d6): δ 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 = 9.5 Hz, 1 H), 5.48 - 5.49 (m, 3H), 5.64 - 5.73 ( m, 4H), 7.18 (t, J = 8.4 Hz, 2H), 7.47 - 7.51 (m, 2H), 7.68 - 7.74 (m, 4H), 8.76 (d, J = 10.3 Hz, 2H).
Step-4:
Figure imgf000080_0001
[00275] (2R,2'R,3R,3'R,4S,4'S,5R,5'R,6S,6'S)-6,6'-selenobis(4-(4-(3- fluorophenyl)-1 H- 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)-selenobis(6- (acetoxymethyl)-4-(4-(3-fluorophenyl) -1 H- 1 ,2,3-triazoM -yl)tetrahydro-2H-pyran- 2,3,5-triyl) tetra acetate (7, 200 mg, 0.21 mmol) in MeOH (10 mL), NaOMe (0.4 mL, 0.42 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was acidified with Amberlyst 15H (pH ~6), filtered, washed with MeOH and concentrated in vacuo. The crude residue was purified by prep-HPLC (reverse phase, X BRIDGE Shield RP, C-18, 19 x 250 mm, 5m, gradient 50% to 82% ACN in water containing 5Mm Ammonium bicarbonate, 214 nm, RT: 7.8 min to afford the title compound as a white solid (GTJC-010-01 , 18 mg).
[00276] LCMS (Method A): m/z 697 (M+H)+ (ES+), at 4.51 min, purity 96%.
[00277] 1H-NMR (400 MHz; DMSO-d6): d 3.49 - 3.61 (m, 4H), 3.72 (t, J = 6.2
Hz, 2H), 3.99 (dd, 2.9 & 6.6 Hz, 2H), 4.36 - 4.43 (m, 2H), 4.70 (t, J = 5.5 Hz, 1 H), 4.82 (dd, 2.8 & 10.5 Hz, 2H), 5.19 (d, J = 9.7 Hz, 2H), 5.31 (d, J = 7.2 Hz, 2H), 5.40 (d, J = 6.6 Hz, 2H), 7.12 - 7.17 (m, 2H), 7.46 - 7.51 (m, 2H), 7.66 (dd, J = 2.3 & 10.2 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 8.67 (s, 2H).
[00278] CMS (Method A): Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 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; Solvents: solvent A = 5 mM ammonium acetate in water; solvent B = acetonitrile; Injection volume 1 L L; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL per min.
[00279] All publications and patents mentioned herein are hereby incorporated by reference in their entireties as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Reference is made to International application No. PCT/US17/20858, filed March 3, 2017, which is incorporated by reference in its entirety.

Claims

1. A method for treatment of 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
Figure imgf000082_0001
Formula (1 )
wherein X is 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 acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein R2, and R3 are independently selected from the group consisting of CO, O2, S O2, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfb group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group.
2. A method for treatment of 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
Figure imgf000084_0001
Formula (2)
wherein X is 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 acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein R2, and R3 are independently selected from the group consisting of CO, O2, SO2, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfb group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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; substituted D-galactose; C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose; hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, and a substituted imino group.
3. A method for treatment of systemic insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general Formula (3) or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000086_0001
Formula (3) wherein X is 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 add, an hydrophobic linear and cydic hydrophobic hydrocarbons derivatives induding heterocydic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocartons derivatives induding heterocydic substitutions of 3 or more atoms,
wherein n£ 24,
wherein R1 and R2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 cartons substituted with a carboxy group, an alkyl group of at least 3 cartons substituted with an amino group, an alkenyl group of at least 3 cartons substituted with an amino group, an alkyl group of at least 3 cartons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 cartons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfb group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted With at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triaZol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group.
4. A method for treatment of systemic insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general Formula (4) or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000088_0001
Formula (4)
wherein X is 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 add, an hydrophobic linear and cydic hydrophobic hydrocarbons derivatives induding heterocydic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2, and hydrophobic hydrocartons derivatives induding heterocydic substitutions of 3 or more atoms,
wherein n£ 24,
wherein R1 and R2 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 cartons substituted with a carboxy group, an alkyl group of at least 3 cartons substituted with an amino group, an alkenyl group of at least 3 cartons substituted with an amino group, an alkyl group of at least 3 cartons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 cartons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfb group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D-galactose, C3-[1 ,2,3]-triaZol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, and a substituted imino group.
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 treatment of systemic insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general Formula (5) or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000090_0001
wherein X is Se, Se-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 acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
wherein R2, R3 and R4 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination 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 carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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, substituted D- galactose, C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, and a substituted imino group.
10. A method for treatment of systemic insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general Formula (6) or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000092_0001
Formula (6) wherein X is Se, Se-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 add an combinations thereof,
wherein Z is selected from the group consisting of O, S, N, CH, Se, S, , P, and hydrophobic hydrocarbons derivatives induding heterocydic substitutions of 3 or more atoms,
wherein R1, R2, R3 and R4 are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 cartons, an alkyl group of at least 3 cartons substituted with a cartoxy group, an alkenyl group of at least 3 cartons substituted with a cartoxy group, an alkyl group of at least 3 cartons substituted with an amino group, an alkenyl group of at least 3 cartons substituted with an amino group, an alkyl group of at least 3 cartons substituted with both an amino and a cartoxy group, an alkenyl group of at least 3 cartons substituted with both an amino and a cartoxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one cartoxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy 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; substituted D- galactose; C3-[1 ,2,3]-triazol-1-yl-substituted D-galactose; hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, and a substituted imino group.
11. The method of any of claims 1-10, wherein the halogen is a fluoro, a chloro, a bromo or an iodo group.
12. A method for treatment of systemic insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (7) or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000094_0001
12. The method of any of claims 1-10 or 12, wherein the compound has a binding affinity for galectins.
13. The method of any of claims 1-10 or 12, wherein the compound has a binding affinity for galectin-3.
14. The method according to any of claims 1-10 or 12, wherein the step of administering comprises administering the compound and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
15. The method of any of claims 1-10 or 12, wherein in the step of administering, the compound is administered in conjunction with an active agent.
16. The method according to any of claims 1-10 or 12, wherein the step of administering comprises administering the compound, a synergistic active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
17. The method of claim 15 or 16, wherein in the step of administering, the active agent is an immunomodulatory, an anti-inflammatory drug, a vitamin, a nutraceutical drug, a supplement, or combinations thereof.
18. The method of any of claims 1 -10 or 12, for treating systemic insulin resistance associated with type 1 diabetes.
19. The method of any of claims 1 -10 or 12, for treating systemic insulin resistance associated with type 2 diabetes mellitus (T2DM).
20. The method of any of claims 1 -10 or 12, for treating systemic insulin resistance associated with obesity, gestational diabetes or prediabetes.
21 . The method of any of claims 1 -10 or 12, wherein treatment with the compound restores sensitivity of cells to insulin activity.
22. The method of any of claims 1-10 or 12, wherein the compound inhibits galectin-3 interaction with Insulin receptor, thereby interfering with insulin binding and cellular glucose uptake mechanism.
23. The method of any of claims 1 -10 or 12, for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD.
24. The method of any of claims 1 -10 or 12, for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance.
25. The method according to any of claims 1 -10 or 12, for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGFb Receptor pathway in kidney chronic disease.
26. The method according to any of claims 1-10 or 12, wherein the compound inhibits overexpression of TGF-b receptor signaling system triggered by Insulin resistance in diabetic and causes deciine in renal function, and/or wherein the compound reverses established lesions of diabetic glomerulopathy. The method according to any of claims 1-10 or 12, for the treatment of obstructive sleep apnea (OSA) associated with insulin resistance obesity and diabetes.
The method according to any of claims 1-10 or 12, wherein the step of administering comprises administering the compound and a synergistic active antidiabetic drug.
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