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WO2024217497A9 - Nouveaux agonistes à petites molécules du récepteur de l'insuline (insr) utilisés en tant que médicaments anti-diabète - Google Patents

Nouveaux agonistes à petites molécules du récepteur de l'insuline (insr) utilisés en tant que médicaments anti-diabète

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Publication number
WO2024217497A9
WO2024217497A9 PCT/CN2024/088584 CN2024088584W WO2024217497A9 WO 2024217497 A9 WO2024217497 A9 WO 2024217497A9 CN 2024088584 W CN2024088584 W CN 2024088584W WO 2024217497 A9 WO2024217497 A9 WO 2024217497A9
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WO
WIPO (PCT)
Prior art keywords
insr
compound
acid
subject
compounds
Prior art date
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Pending
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PCT/CN2024/088584
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English (en)
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WO2024217497A1 (fr
Inventor
Yiran HUANG
Xiaoyu Li
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University of Hong Kong HKU
Laboratory for Synthetic Chemistry and Chemical Biology Ltd
Original Assignee
University of Hong Kong HKU
Laboratory for Synthetic Chemistry and Chemical Biology Ltd
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Application filed by University of Hong Kong HKU, Laboratory for Synthetic Chemistry and Chemical Biology Ltd filed Critical University of Hong Kong HKU
Priority to CN202480027096.2A priority Critical patent/CN121002044A/zh
Publication of WO2024217497A1 publication Critical patent/WO2024217497A1/fr
Publication of WO2024217497A9 publication Critical patent/WO2024217497A9/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic

Definitions

  • Diabetes mellitus is a group of metabolic disorder diseases manifested by abnormally high blood sugar level (hyperglycemia) over a prolonged period of time. Diabetes is a chronic disease caused by disorder of carbohydrate metabolism, which may further cause multiple severe complications. Diabetes has plagued a large percentage of the world population for centuries. Hence, effective anti-diabetes drugs are highly desired.
  • Insulin receptor is a transmembrane protein that belongs to the receptor tyrosine kinase (RTK) superfamily proteins.
  • RTK receptor tyrosine kinase
  • the insulin level in blood will be upregulated. Binding of insulin to INSR activates the intracellular INSR auto-phosphorylation, which will further trigger a cascade of downstream cell signaling pathways and eventually facilitate cellular uptake of glucose to reduce the blood glucose level. Hyposecretion or dysfunctions of insulin-mediated INSR activation may result in serious diseases, such as, for example diabetes and malignant cancers. Thus, insulin-alternative drugs, especially orally available ones, are of high significance in diabetes treatment. However, INSR-targeting small molecule drugs remain largely underexplored.
  • INSR insulin receptor
  • peptides and peptidomimetics whose structures are based on insulin; thus, they typically have poor oral bioavailability and have to be administrated by injection.
  • injection drugs suffer from high costs and poor patience compliance. Therefore, novel INSR agonist drugs, particularly orally available drugs, are urgently needed.
  • This invention pertains to a novel compounds, compositions containing the novel compounds, and methods of activating in insulin receptor (INSR) , particularly in the context of treating diabetes.
  • the subject compounds and compositions can bind to an allosteric site on INSR and are synergistic with insulin in activating INSR and the downstream signaling pathways.
  • the compounds have a low systemic toxicity and can be used in combination with the traditional insulin therapy for the treatment of diabetes.
  • the compounds of the subject invention are INSR agonists.
  • the subject compounds can bind to an allosteric site on the INSR protein, stabilize the receptor in an active conformation, activate the receptor, and eventually stimulate the downstream signaling pathways in cells.
  • the pathways activated by the subject compounds play key roles in homeostasis of blood sugar levels; therefore, the subject compounds can be used to treat diabetes or other diseases related to high blood sugar, such as, for example, obesity.
  • the compounds and/or compositions of subject invention can be used in methods of activating the INSR protein and/or treating diabetes comprising the step of administering therapeutically effect amounts of the compounds or compositions disclosed herein to a subject in need thereof.
  • the subject compounds have a low molecular weight. In certain embodiments, the molecular weights of the subject compounds can range from about 720 Da to about 822 Da.
  • the compounds of the subject invention can show clear agonistic effect on INSR phosphorylation level either by themselves or synergetic with the natural agonist insulin. Furthermore, the compounds can upregulate the phosphorylation level of insulin receptor substrate (IRS-1) and protein kinase B (Akt) , two key downstream proteins in the INSR signaling pathway.
  • IRS-1 insulin receptor substrate
  • Akt protein kinase B
  • FIG. 1 The screening of a 30-million-compound chemical library against INSR on live cells.
  • the INSR is activated and stabilized with insulin.
  • the intracellular phosphorylation site is used as an affinity handle to isolate the potential agonists bound to the activated INSR, which are further identified and characterized.
  • FIGs. 2A-2C Chemical structures of the discovered novel INSR agonists.
  • FIG. 2A refers to I-6;
  • FIG. 2B refers to I-8; and
  • FIG. 2C refers to I-9.
  • FIGs. 3A-3C Compounds I-6, I-8, and I-9 were tested for their agonistic activities on INSR phosphorylation level.
  • FIG. 3A I-6 testing results
  • FIG. 3B I-8 testing results
  • FIG. 3C I-9 testing results.
  • Left panels phosphorylation level of INSR pY1355
  • right panels phosphorylation level of INSR pY1361.
  • the concentrations of the compounds and insulin used are as marked.
  • n 3 biologically independent samples; data are presented as mean values ⁇ s. d.
  • FIGs. 4A-4B Compounds I-8, and I-9 were tested for their effects on the phosphorylation level of the proteins (Akt and IRS1) downstream in the INSR-mediated signaling pathway; phosphorylation is the marker of protein activation.
  • FIG. 4A The activating effect of I-8 on Akt and IRS1;
  • FIG. 4B the activating effect of I-9 on Akt and IRS1.
  • FIG. 5 Schematic illustration of the general synthesis scheme of the identified INSR agonists.
  • compositions containing amounts of ingredients where the terms “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10%around the value (X ⁇ 10%) . In other contexts the term “about” is used provides a variation (error range) of 0-10%around a given value (X ⁇ 10%) .
  • this variation represents a range that is up to 10%above or below a given value, for example, X ⁇ 1%, X ⁇ 2%, X ⁇ 3%, X ⁇ 4%, X ⁇ 5%, X ⁇ 6%, X ⁇ 7%, X ⁇ 8%, X ⁇ 9%, or X ⁇ 10%.
  • ranges are stated in shorthand to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.
  • a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc.
  • a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values.
  • ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included.
  • treatment refers to eradicating, reducing, ameliorating, or reversing a sign or symptom of a health condition, disease or disorder to any extent, and includes, but does not require, a complete cure of the condition, disease, or disorder. Treating can be curing, improving, or partially ameliorating a disorder. “Treatment” can also include improving or enhancing a condition or characteristic, for example, bringing the function of a particular system in the body to a heightened state of health or homeostasis.
  • reduces is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.
  • an “isolated” or “purified” compound is substantially free of other compounds.
  • purified compounds are at least 60%by weight (dry weight) of the compound of interest.
  • the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight of the compound of interest.
  • a purified compound is one that is at least 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, or 100% (w/w) of the desired compound by weight. Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography, or high-performance liquid chromatography (HPLC) analysis.
  • the terms “therapeutically-effective amount, ” “therapeutically-effective dose, ” “effective amount, ” and “effective dose” are used to refer to an amount or dose of a compound or composition thereof that, when administered to a subject, is capable of treating or improving a condition, disease, or disorder in a subject or that is capable of providing enhancement in health or function to an organ, tissue, or body system. In other words, when administered to a subject, the amount is “therapeutically effective.
  • the actual amount will vary depending on a number of factors including, but not limited to, the particular condition, disease, or disorder being treated or improved; the severity of the condition; the particular organ, tissue, or body system of which enhancement in health or function is desired; the weight, height, age, and health of the patient; and the route of administration.
  • the terms “reducing” , “inhibiting” , “blocking” , “preventing” , “alleviating” , or “relieving” when referring to a compound mean that the compound brings down the occurrence, severity, size, volume or associated symptoms of diabetes by at least about 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 100%compared to how diabetes would normally exist without application of the compound or a composition comprising the compound.
  • the terms “agonizing” , “enhancing” , or “activating” when referring to a compound mean that the compound brings up the amount or expression or phosphorylation levels of a protein by at least about 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 100%compared to how the amount or expression or phosphorylation levels of a protein would normally exist without application of the compound or a composition comprising the compound.
  • diabetes refers to a group of disorders characterized by excess sugar in the blood.
  • Diabetes can include chronic diabetes, such as, for example type 1 diabetes or type 2 diabetes. Diabetes can also include prediabetes and gestational diabetes.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts that are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • a “pharmaceutically acceptable vehicle” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used to facilitate administration of an agent and that is compatible therewith.
  • examples of vehicles include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the method comprises administration of multiple doses of the compositions of the subject invention.
  • the method may comprise administration of therapeutically effective doses of a composition comprising the compound or composition thereof of the subject invention as described herein four times a day, thrice a day, twice a day, once a day, every other day, three times a week, once a week, or a lower frequency.
  • doses are administered over the course of 1 week, 2 weeks, or more than 3 weeks.
  • treatment of a subject with a therapeutically effective amount of the compositions of the invention can include a single treatment or can include a series of treatments.
  • the effective dosage of a compound or composition thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays for blood sugar levels and/or phosphorylation levels of INSR, which are known in the art. Specifically, the phosphorylation level of INSR can be measured by harvesting cells, lysing the cells, and measuring the INSR phosphorylation level using the specific antibodies in Western blot experiments.
  • the method comprises administration of the compositions at several time per day, including but not limiting to 2 times per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day, 7 times per day, 8 times per day, 9 times per day, and 10 times per day.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • the compounds provided herein can activate or agonize the insulin receptor (INSR) protein.
  • the compounds provided can also treat diabetes or related ailments and symptoms thereof.
  • Pharmaceutically acceptable salts can be a salt with an inorganic acid, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid; an organic acid, such as trifluoroacetic acid (TFA) , formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid; or a salt with a base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines, and substituted ethanolamines.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • an organic acid such as trifluoroacetic acid (TF
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • Hydrate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • Solvate means a solvate formed from the association of one or more solvent molecules to a compound of the present invention.
  • the term "solvate includes hydrates (e.g., mono hydrate, dihydrate, trihydrate, tetrahydrate, and the like) .
  • Certain embodiments provide amorphous forms of salts of the compounds disclosed herein. Such amorphous forms are advantageous for oral, pulmonary, buccal, intravaginal, or suppository delivery. In preferred embodiments, the subject compounds are administered orally.
  • Orally consumable products according to the invention are any preparations or compositions suitable for consumption, for nutrition, for oral hygiene, or for pleasure, and are products intended to be introduced into the human or animal oral cavity, to remain there for a certain period of time, and then either be swallowed (e.g., food ready for consumption or pills) or to be removed from the oral cavity again (e.g., chewing gums or products of oral hygiene or medical mouth washes) .
  • an orally-deliverable pharmaceutical can be formulated into an orally consumable product, and an orally consumable product can comprise an orally deliverable pharmaceutical, the two terms are not meant to be used interchangeably herein.
  • Orally consumable products include all substances or products intended to be ingested by humans or animals in a processed, semi-processed, or unprocessed state. This also includes substances that are added to orally consumable products (particularly food and pharmaceutical products) during their production, treatment, or processing and intended to be introduced into the human or animal oral cavity.
  • Orally consumable products can also include substances intended to be swallowed by humans or animals and then digested in an unmodified, prepared, or processed state; the orally consumable products according to the invention therefore also include casings, coatings, or other encapsulations that are intended to be swallowed together with the product or for which swallowing is to be anticipated.
  • the orally consumable product is a capsule, pill, syrup, emulsion, or liquid suspension containing a desired orally deliverable substance.
  • the orally consumable product can comprise an orally deliverable substance in powder form, which can be mixed with water or another liquid to produce a drinkable orally-consumable product.
  • the orally-consumable product according to the invention can comprise one or more formulations intended for nutrition or pleasure.
  • these particularly include baking products (e.g., bread, dry biscuits, cake, and other pastries) , sweets (e.g., chocolates, chocolate bar products, other bar products, fruit gum, coated tablets, hard caramels, toffees and caramels, and chewing gum) , alcoholic or non-alcoholic beverages (e.g., cocoa, coffee, green tea, black tea, black or green tea beverages enriched with extracts of green or black tea, Rooibos tea, other herbal teas, fruit-containing lemonades, isotonic beverages, soft drinks, nectars, fruit and vegetable juices, and fruit or vegetable juice preparations) , instant beverages (e.g., instant cocoa beverages, instant tea beverages, and instant coffee beverages) , meat products (e.g., ham, fresh or raw sausage preparations, and seasoned or marinated fresh meat or salted meat products) , eggs or egg products (e.g.,
  • the subject composition can further comprise one or more pharmaceutically acceptable carriers, and/or excipients, and can be formulated into preparations, for example, solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.
  • pharmaceutically acceptable carriers such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.
  • pharmaceutically acceptable means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.
  • Carriers and/or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers) , oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80) , colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione) , amino acids (e.g., glycine) , proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatizers, thickeners (e.g.
  • buffers
  • compositions of the subject invention can be made into aerosol formulations so that, for example, it can be nebulized or inhaled.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, powders, particles, solutions, suspensions or emulsions.
  • Formulations for oral or nasal aerosol or inhalation administration may also be formulated with carriers, including, for example, saline, polyethylene glycol or glycols, DPPC, methylcellulose, or in mixture with powdered dispersing agents or fluorocarbons.
  • Aerosol formulations can be placed into pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • delivery may be by use of a single-use delivery device, a mist nebulizer, a breath-activated powder inhaler, an aerosol metered-dose inhaler (MDI) , or any other of the numerous nebulizer delivery devices available in the art.
  • MDI aerosol metered-dose inhaler
  • mist tents or direct administration through endotracheal tubes may also be used.
  • compositions of the subject invention can be formulated for administration via injection, for example, as a solution or suspension.
  • the solution or suspension can comprise suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1, 3-butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono-or diglycerides, and fatty acids, including oleic acid.
  • a carrier for intravenous use includes a mixture of 10%USP ethanol, 40%USP propylene glycol or polyethylene glycol 600 and the balance USP Water for Injection (WFI) .
  • WFI Water for Injection
  • Other illustrative carriers for intravenous use include 10%USP ethanol and USP WFI; 0.01-0.1%triethanolamine in USP WFI; or 0.01-0.2%dipalmitoyl diphosphatidylcholine in USP WFI; and 1-10%squalene or parenteral vegetable oil-in-water emulsion. Water or saline solutions and aqueous dextrose and glycerol solutions may be preferably employed as carriers, particularly for injectable solutions.
  • Illustrative examples of carriers for subcutaneous or intramuscular use include phosphate buffered saline (PBS) solution, 5%dextrose in WFI and 0.01-0.1%triethanolamine in 5%dextrose or 0.9%sodium chloride in USP WFI, or a 1 to 2 or 1 to 4 mixture of 10%USP ethanol, 40%propylene glycol and the balance an acceptable isotonic solution such as 5%dextrose or 0.9%sodium chloride; or 0.01-0.2%dipalmitoyl diphosphatidylcholine in USP WFI and 1 to 10%squalene or parenteral vegetable oil-in-water emulsions.
  • PBS phosphate buffered saline
  • compositions of the subject invention can be formulated for administration via topical application onto the skin, for example, as topical compositions, which include rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch.
  • topical compositions which include rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch.
  • Suitable formulations of topical applications can comprise in addition to any of the pharmaceutically active carriers, for example, emollients such as carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrous lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax.
  • emollients such as carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrous lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax.
  • compositions may contain humectants such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1, 2, 6 hexanetriol or permeation enhancers such as ethanol, isopropyl alcohol, or oleic acid.
  • humectants such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1, 2, 6 hexanetriol or permeation enhancers such as ethanol, isopropyl alcohol, or oleic acid.
  • the cells were lysed with modified RIPA buffer (supplemented with Universal nuclease, Abcam EDTA-free Protease Inhibitor Cocktail and Abcam Phosphatase Inhibitor Cocktail IV) at 4 °C for 15 min.
  • Cell lysates were obtained by collecting the supernatant after centrifugation at 13, 300 rpm for 10 min to remove insoluble cell debris. The protein concentration was determined with a BCA Protein Assay Kit.
  • HEK293 cells were cultured on 12-well plates at 37 °C and transfected with PCMV3-INSR-long-t1-HA for 24 h, followed by serum-starvation for 24 h to reduce intrinsic INSR phosphorylation levels. Starved cells were treated with 300 ⁇ L compound-saturating DMEM in the absence of FBS at 37 °C for 30 min.
  • the cells were washed with ice-cold 1x PBS buffer (supplemented with Abcam Phosphatase Inhibitor Cocktail IV) and lysed on plate with modified RIPA buffer (supplemented with Universal nuclease, Abcam EDTA-free Protease Inhibitor Cocktail and Abcam Phosphatase Inhibitor Cocktail IV) at 4 °C for 15 min.
  • Cell lysates were obtained by collecting the supernatant after centrifugation at 13, 300 rpm for 10 min to remove insoluble cell debris. The protein concentration was determined with a BCA Protein Assay Kit.
  • the cell lysates were resolved with SDS-PAGE and electro-transferred onto immune-blot PVDF membranes.
  • the membrane was blocked with 5 %non-fat milk in TBST buffer, incubated with the Phospho-INSR (Tyr1355) Polyclonal Antibody, Phospho-INSR (Tyr1361) Polyclonal Antibody and INSR Polyclonal Antibody respectively, followed by incubation with HRP-conjugated goat anti-rabbit IgG antibody.
  • the membranes were developed with ClarityTM Western ECL Substrate.
  • the linear tripeptide was assembled on 2-chlorotrityl resin (0.1 mmol, loading of 1.0 mmol/g, GL Biochem, Lot No: GLS190613-48101) using the general procedure in the following sequence: N-alpha-Fmoc-N-gamma-trityl-D-asparagine (Accela, Catalog: SY042590, CAS no: 180570-71-2) , N-Fmoc-N'-tosyl-L-arginine (NJPeptide, Catalog: R30203, CAS no: 83792-47-6) , 2, 4-Dihydroxypyrimidine-5-carboxylic acid (J&K Scientific, Catalog: 104951, CAS no: 23945-44-0) .
  • the peptide was released from the resin using a cleavage solution of TFE/AcOH/DCM (1: 1: 8) . Afterwards, the solvent, acid and TFE was removed by evaporation and the product was dissolved by CH 3 CN/H 2 O (1: 1) followed by reverse-phase HPLC purification. The desired tripeptide INSR-6 was recovered as a white powder after lyophilization (60.0 mg, 73%yield) .
  • the linear tripeptide was assembled on 2-chlorotrityl resin (0.1 mmol, loading of 1.0 mmol/g, GL Biochem, Lot No: GLS190613-48101) using the general procedure in the following sequence: N-alpha-Fmoc-N-gamma-trityl-L-asparagine (Bidepharm, Catalog: BD8578-25g, CAS no: 132388-59-1) , N-Fmoc-3-nitro-L-tyrosine Bidepharm, Catalog: BD18164-10g, CAS no: 136590-09-5) , 2, 4-Dihydroxypyrimidine-5-carboxylic acid (J&K Scientific, Catalog: 104951, CAS no: 23945-44-0) .
  • the peptide was released from the resin using a cleavage solution of TFE/AcOH/DCM (1: 1: 8) . Afterwards, the solvent, acid and TFE was removed by evaporation and the product was dissolved by CH3CN/H2O (1: 1) followed by reverse-phase HPLC purification. The desired tripeptide INSR-8 was recovered as a white powder after lyophilization (48.6mg, 67.5%yield) .
  • the linear tripeptide was assembled on 2-chlorotrityl resin (0.1 mmol, loading of 1.0 mmol/g, GL Biochem, Lot No: GLS190613-48101) using the general procedure in the following sequence: N-alpha-Fmoc-N-in-Boc-D-tryptophan (Dieckmann, Catalog: MD00229, CAS no: 163619-04-3) , N-Fmoc-N'-tosyl-L-arginine (NJPeptide, Catalog: R30203, CAS no: 83792-47-6) , 2, 4-Dihydroxypyrimidine-5-carboxylic acid (J&K Scientific, Catalog: 104951, CAS no: 23945-44-0) .
  • the peptide was released from the resin using a cleavage solution of TFE/AcOH/DCM (1: 1: 8) . Afterwards, the solvent, acid and TFE was removed by evaporation and the product was dissolved by CH 3 CN/H 2 O (1: 1) followed by reverse-phase HPLC purification. The desired tripeptide INSR-9 was recovered as a white powder after lyophilization (43.8 mg, 58%yield) .
  • FIGs. 2A-2C show a series of small molecule agonists for INSR (three representatives, I-6 (formula (II) ) , I-8 (formula (III) ) , and I-9 (formula (IV) ) , are shown in FIGs. 2A-2C) .
  • the compounds showed clear agonistic effect on INSR phosphorylation level either by themselves or synergetic with the natural agonist insulin (FIGs. 3A-3C) . Furthermore, these compounds were able to upregulate the phosphorylation level of insulin receptor substrate (IRS-1) and protein kinase B (Akt) , two key downstream proteins in the INSR signaling pathway (FIGs. 4A-4B) .
  • IRS-1 insulin receptor substrate
  • Akt protein kinase B

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne de nouveaux composés, des compositions contenant les nouveaux composés, et des procédés d'activation dans le récepteur de l'insuline (INSR), en particulier dans le contexte du traitement du diabète. Les composés et compositions selon l'invention peuvent se lier à un site allostérique sur INSR et sont synergiques avec l'insuline pour activer l'INSR et les voies de signalisation en aval par phosphorylation de la protéine INSR.
PCT/CN2024/088584 2023-04-21 2024-04-18 Nouveaux agonistes à petites molécules du récepteur de l'insuline (insr) utilisés en tant que médicaments anti-diabète Pending WO2024217497A1 (fr)

Priority Applications (1)

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CN202480027096.2A CN121002044A (zh) 2023-04-21 2024-04-18 作为抗糖尿病药物的新型胰岛素受体(insr)小分子激动剂

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US202363497484P 2023-04-21 2023-04-21
US63/497484 2023-04-21

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WO2024217497A9 true WO2024217497A9 (fr) 2025-10-09

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PCT/CN2024/088584 Pending WO2024217497A1 (fr) 2023-04-21 2024-04-18 Nouveaux agonistes à petites molécules du récepteur de l'insuline (insr) utilisés en tant que médicaments anti-diabète

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BRPI0407507A (pt) * 2003-02-13 2006-02-14 Aventis Pharma Gmbh derivados de hexahidro-pirazino[1,2-a]pirimidin-4,7-diona, processos para sua preparação de sua aplicação como medicamento
JP2013010750A (ja) * 2011-06-02 2013-01-17 Taisho Pharmaceutical Co Ltd ２−ピリドン化合物を含有する医薬
MX2020009950A (es) * 2018-03-23 2021-04-28 Carmot Therapeutics Inc Moduladores de receptores acoplados a proteina g.
MX2022013619A (es) * 2020-05-01 2022-11-16 Gilead Sciences Inc Compuestos de 2,4-dioxopirimidina que inhiben cd73.

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