WO2020137880A1 - オキシトシン誘導体及びその使用 - Google Patents

オキシトシン誘導体及びその使用 Download PDF

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WO2020137880A1
WO2020137880A1 PCT/JP2019/050089 JP2019050089W WO2020137880A1 WO 2020137880 A1 WO2020137880 A1 WO 2020137880A1 JP 2019050089 W JP2019050089 W JP 2019050089W WO 2020137880 A1 WO2020137880 A1 WO 2020137880A1
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compound
oxytocin
compounds
hotr
administration
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PCT/JP2019/050089
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English (en)
French (fr)
Japanese (ja)
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陽博 東田
横山　茂
スタニスラフ ミハイロヴィチ チェレパノフ
周東　智
亘 一ノ瀬
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国立大学法人北海道大学
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Priority to JP2020563200A priority Critical patent/JP7390031B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/16—Oxytocins; Vasopressins; Related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring

Definitions

  • the present invention relates to an oxytocin derivative and its use. More specifically, the present invention relates to a novel oxytocin derivative, oxytocin receptor agonist, and oxytocin receptor agonist pharmaceutical composition.
  • the present application claims priority based on Japanese Patent Application No. 2018-246141 filed in Japan on December 27, 2018, and the content thereof is incorporated herein.
  • Oxytocin (CAS number: 50-56-6) is a compound represented by the following formula (A), which is a peptide hormone secreted from the posterior pituitary.
  • Oxytocin is present in peripheral organs such as the uterus and mammary gland and in the central nervous system, and is known to induce uterine contraction and lactation. Oxytocin is also known to enhance social communication such as social behavior, cognition and memory in mammals including humans.
  • autism spectrum disorder is a congenital disease characterized by social communication, social interaction, repetitive behavior, limited interest, etc.
  • ASD autism spectrum disorder
  • Oxytocin may be associated with abnormal social communication behavior in ASD patients.
  • ASD patients have been reported to have low levels of oxytocin in blood or salivary glands.
  • high frequency gene mutations are detected in the coding region and non-coding region of the oxytocin receptor in ASD patients.
  • CD38 which is a transmembrane protein related to oxytocin signal transduction, causes autism-like symptoms in mice.
  • the single nucleotide polymorphism of CD38 is associated with ASD.
  • oxytocin may be a valuable lead compound for the development of new drugs that restore normal social behavior in patients with neurodevelopmental disorders or psychiatric disorders.
  • Carbetocin (CAS number: 37025-55-1) is a derivative of oxytocin and is used as a uterine contractor together with oxytocin.
  • oxytocin and carbetocin lack selectivity for vasopressin receptors, particularly V 2 receptors. Therefore, side effects such as antidiuresis and hyponatremia may be observed during administration of oxytocin and carbetocin.
  • the present invention aims to provide a novel oxytocin derivative.
  • a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof (wherein, in the following formula (1), X is a sulfur atom or a methylene group, and R 3 is It is a group represented by the following formula (2) or the following formula (3).
  • An oxytocin receptor agonist comprising the compound according to [1], a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • the oxytocin receptor agonist according to [2] which is a therapeutic agent for neurodevelopmental disorders or mental disorders or a uterine contractor.
  • An oxytocin receptor agonist pharmaceutical composition comprising the oxytocin receptor agonist according to [2] or [3] and a pharmacologically acceptable carrier.
  • a novel oxytocin derivative can be provided.
  • FIG. 9 is a graph showing the results of a radiation competition assay in Experimental Example 2.
  • (A)-(d) is a graph showing the measurement results of intracellular calcium ion concentration in Experimental Example 3.
  • 9 is a graph showing the results of the tail suspension test in Experimental Example 5.
  • (A) And (b) is a graph which shows the result of having quantified the consumption of water and a sucrose solution in Experimental example 6.
  • (A) to (c) are graphs showing the results of measuring the plasma concentration of each compound in Experimental Example 7.
  • 9 is a graph showing the measurement results of the plasma concentration of each compound in Experimental Example 8.
  • (A)-(c) is a graph showing the exercise competition curve measured in Experimental Example 9.
  • 11 is a graph showing the results of measuring the uterine contractility inducing effect of each compound in Experimental Example 10.
  • the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • X is a sulfur atom or a methylene group
  • R 3 is a group represented by the following formula (2) or the following formula (3).
  • X is preferably a sulfur atom.
  • R 3 is a group represented by the above formula (2) (hereinafter, referred to as “compound 2”).
  • having a super agonist activity means having an agonist activity having a higher oxytocin receptor activation ability than oxytocin, which is a natural ligand for the oxytocin receptor.
  • the chemical formula of compound 2 is shown in the following formula (4).
  • the inventors of the present invention have a compound in which X is a sulfur atom and R 3 is a group represented by the formula (3) (hereinafter, may be referred to as “compound 5”).
  • compound 5 was an agonist showing a long-term and lasting activation effect on the oxytocin receptor.
  • the term “long term” means that the duration of activation of the oxytocin receptor is longer than that of oxytocin, which is a natural ligand for the oxytocin receptor, and for example, even after 24 hours after acting on the oxytocin receptor. It may be that the activation effect of the oxytocin receptor is maintained.
  • the chemical formula of compound 5 is shown in the following formula (5).
  • examples of the pharmaceutically acceptable salt include salts commonly used pharmaceutically, and examples thereof include metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. More specifically, for example, hydrochloride, sulfate, hydrobromide, nitrate, inorganic acid salt such as phosphate, acetate, mesylate, succinate, maleate, fumarate, Organic acid salts such as citrate and tartrate, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, metal salts such as aluminum salt and zinc salt, ammonium salt, tetra salt Examples thereof include ammonium salts such as methylammonium salt, organic amine addition salts such as morpholine and piperidine, amino acid addition salts such as glycine, phenylalanine, lysine, aspartic acid and glutamic acid.
  • solvate of the compound represented by formula (1) and the solvate of the salt of the compound represented by formula (1) are not particularly limited as long as they are pharmaceutically acceptable solvates. Examples include hydrates and organic solvates.
  • the present invention provides an oxytocin receptor agonist comprising a compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • the inventors have clarified that the compound represented by the above formula (1) has an agonistic activity on the oxytocin receptor.
  • the compound 2 represented by the above formula (4) exhibits superagonist activity on the oxytocin receptor.
  • the compound 5 represented by the above formula (5) is an agonist that exhibits a long-lasting activating effect on the oxytocin receptor.
  • the salts and solvates of the oxytocin receptor agonist of the present embodiment are the same as those described above.
  • the oxytocin receptor agonist may be a therapeutic agent for neurodevelopmental disorders or mental disorders, or a uterine contractile agent.
  • Neurodevelopmental disorders or mental disorders include autism spectrum disorder (ASD; Asperger's syndrome, high functioning autism, autism including Kanner's syndrome), schizophrenia, attention deficit hyperactivity disorder (ADHD), Parkinson's disease Mental disorders associated with autism spectrum disorder (ASD; Asperger's syndrome, high functioning autism, autism including Kanner's syndrome), schizophrenia, attention deficit hyperactivity disorder (ADHD), Parkinson's disease Mental disorders associated with autism spectrum disorder (ASD; Asperger's syndrome, high functioning autism, autism including Kanner's syndrome), schizophrenia, attention deficit hyperactivity disorder (ADHD), Parkinson's disease Mental disorders associated with ASD; Asperger's syndrome, high functioning autism, autism including Kanner's syndrome), schizophrenia, attention deficit hyperactivity disorder (ADHD), Parkinson's disease Mental disorders associated with ADHD and others.
  • ADHD attention deficit hyperactivity disorder
  • the uterine contractile agent can be used as a hemostatic agent (uterine contractile hemostatic agent) or the like that induces labor, promotes labor, and prevents blood loss from the uterus after labor.
  • the above-mentioned oxytocin receptor agonist may be formulated as a oxytocin receptor agonist-containing pharmaceutical composition containing a pharmacologically acceptable carrier.
  • the above-mentioned pharmaceutical composition is orally administered in the form of tablets, capsules, elixirs, microcapsules and the like, or parenterally in the form of injections, suppositories, external preparations for the skin, etc.
  • the external preparation for skin include dosage forms such as ointments and patches.
  • binders such as gelatin, corn starch, tragacanth gum, gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injection such as water, ethanol and glycerin;
  • adhesives such as rubber-based adhesives and silicone-based adhesives.
  • the pharmaceutical composition may contain additives.
  • additives such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and maltitol; flavoring agents such as peppermint and red oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid Examples thereof include buffers such as salts and sodium acetate; solubilizing agents such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives.
  • the pharmaceutical composition is prepared by admixing the above-mentioned oxytocin receptor agonist and the above-mentioned pharmaceutically acceptable carrier and additive in an appropriate combination in a unit dose form required for generally accepted pharmaceutical practice. Can be converted.
  • the dose of the pharmaceutical composition varies depending on the symptoms, weight, age, sex, etc. of the patient and cannot be determined unconditionally, but in the case of oral administration, for example, 0.1 to 100 ⁇ g/kg body weight per unit dosage form is used.
  • the active ingredient (oxytocin receptor agonist) may be administered. In the case of an injection, for example, 0.01 to 50 ⁇ g/kg body weight of the active ingredient may be administered per dosage unit form.
  • the daily dose of the pharmaceutical composition varies depending on the symptoms, weight, age, sex, etc. of the patient and cannot be determined unconditionally, but for example, an adult dose of 0.1-100 ⁇ g/kg body weight is effective.
  • the components may be administered once a day or in 2 to 4 divided doses.
  • the present invention provides a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof for use as a medicine (in the above formula (1), X is a sulfur atom or a methylene group, and R 3 is a group represented by the above formula (2) or the above formula (3).
  • the present invention provides a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof for treating a neurodevelopmental disorder or a psychiatric disorder (the above formula ( 1), X is a sulfur atom or a methylene group, and R 3 is a group represented by the above formula (2) or the above formula (3).
  • the present invention provides a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof for the treatment of blood loss from the uterus (the above formula (1)
  • X is a sulfur atom or a methylene group
  • R 3 is a group represented by the above formula (2) or the above formula (3).
  • the present invention provides a compound represented by the above formula (1) for producing a therapeutic agent for neurodevelopmental disorder or psychiatric disorder or a uterine contractor, a pharmaceutically acceptable salt thereof, or a salt thereof.
  • a solvate in the above formula (1), X is a sulfur atom or a methylene group, and R 3 is a group represented by the above formula (2) or the above formula (3) is provided.
  • the present invention provides a compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof (wherein, X is a sulfur atom or a methylene group).
  • R 3 is a group represented by the above formula (2) or the above formula (3).
  • the present invention provides a compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof (wherein, X is a sulfur atom or a methylene group).
  • R 3 is a group represented by the above formula (2) or the above formula (3).
  • a linear peptide was synthesized on a resin by a general solid-phase peptide synthesis method using a 9-fluorenylmethyloxycarbonyl group (Fmoc group) as a protecting group.
  • Fmoc group 9-fluorenylmethyloxycarbonyl group
  • Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt) were used as protected amino acids.
  • -OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH were used.
  • a piperidine/DMF (1:4) solution was used for the removal of the Fmoc group.
  • a mixed solution of TFA (trifluoroacetic acid)/TIS (triisopropylsilane)/water (99:2:2) was used to cut out the protected peptide from the resin.
  • the obtained cyclic peptide was subjected to catalytic hydrogenation reaction in a mixed solvent of ethanol/methanol with 10% Pd-C (0.1 equivalent) and hydrogen at 1 atm, and the reverse After purification by phase HPLC (water-acetonitrile solvent containing 0.1% TFA), the deprotected desired compounds 3 and 6 were obtained as the trifluoroacetate salt.
  • the chemical formula of compound 3 is shown in the following formula (6).
  • the chemical formula of compound 6 is shown in the following formula (7).
  • FIG. 1 is a graph showing the results of a radiation competition assay.
  • OT represents oxytocin
  • AVP represents vasopressin
  • 1” to “6” represent compounds 1 to 6, respectively.
  • the horizontal axis of FIG. 1 represents the concentration of each compound, and the vertical axis represents the ratio (%) of the remaining [ 3 H]oxytocin.
  • Table 2 also shows the results of the radiation binding assay.
  • Compounds other than compound 2 showed slightly lower binding affinity compared to the binding affinity of oxytocin for hOTR.
  • Free Ca 2+ ion concentration was measured using a fluorescent probe, fura-2/AM, and a fluorescent microscope. The measurement results of the free Ca 2+ ion concentration are shown in FIGS. 2(a) to (d). Table 3 shows the EC 50 , selectivity, and E max of each compound calculated based on the measurement results of the free Ca 2+ ion concentration.
  • FIG. 2( a) is a graph showing the measurement results of the agonist activity of Compound 2 against hOTR, hV 1a R and hV 1b R.
  • FIG. 2( b) is a graph showing the measurement results of the agonist activity of Compound 5 against hOTR, hV 1a R and hV 1b R.
  • OTR indicates HOTR
  • V 1A denotes the hV 1a R
  • V 1B indicates the hV 1b R
  • the horizontal axis represents the concentration of each compound and the vertical axis shows the proportion (%) of the free Ca 2+ ion concentration in the case of the free Ca 2+ ion concentration in the case of addition of oxytocin as 100%.
  • FIG. 2(c) is a graph showing the measurement results of hOTR activation by oxytocin, vasopressin, compound 2 and compound 5.
  • OT indicates oxytocin
  • AVP indicates vasopressin
  • 2 indicates compound 2
  • 5 indicates compound 5
  • the horizontal axis indicates the concentration of each compound.
  • the vertical axis shows the proportion (%) of the free Ca 2+ ion concentration in the case of the free Ca 2+ ion concentration in the case of addition of oxytocin as 100%.
  • FIG. 2( d) is a graph showing the measurement results of hV 1a R activation by oxytocin, vasopressin, compound 2 and compound 5.
  • OT represents oxytocin
  • AVP represents vasopressin
  • 2 represents compound 2
  • 5 represents compound 5
  • the horizontal axis represents the concentration of each compound.
  • the vertical axis shows the proportion (%) of the free Ca 2+ ion concentration in the case of the free Ca 2+ ion concentration in the case of addition of vasopressin as 100%.
  • the hOTR selectivity for hV 1a R and hV 1b R was slightly different.
  • Oxytocin, compounds 2 and 3, showed an approximately 20-75 fold increase in selectivity for hOTR over hV 1a R.
  • Carbetocin showed an approximately 200-fold increased selectivity for hOTR over hV 1a R.
  • Compounds 1, 4, 5 and 6 showed >1000-fold increased selectivity for hOTR over hV 1a R.
  • the data for compounds 1 and 4 (Table 2) were in good agreement with the reported values.
  • the selectivity of hOTR for hV 1a R of compound 4 was high, but the selectivity of hOTR for hV 1b R was not high.
  • CD38KOCC mouse a mouse that knocked out CD38 by editing the genome.
  • the sgRNA was designed to target exon 2 of the Cd38 locus.
  • hCas9 mRNA and sgRNA were synthesized using an in vitro RNA transcription kit (trade name “mMESSAGE mMACHINE T7 Transcription Kit", Thermo Fisher Scientific Co.) and an electroporator (model “NEPA21”, NEPA GENE Co.) was used. Introduced into mouse eggs.
  • DNA was isolated from the F 0 generation mouse tail, PCR was used to amplify the genomic region spanning the sgRNA binding site, and individuals having a mutation in the Cd38 gene were screened. Then, 30 or more pups were screened using a commercially available kit (trade name "Guide-it Mutation detection kit", Takara Bio Inc.). As a result, pups having a 2-base pair insertion in the Cd38 gene were identified. This insertion forms a stop codon within the open reading frame of the Cd38 gene, resulting in a loss-of-function mutation of the Cd38 gene.
  • the pups of CD38KOCC mice were weaned at 21 to 28 days of age, and were kept in the same sex group of 5 mice under the standard conditions of 24° C., 12 hours of light/dark cycle, and lighting at 8:00 am, and used in the experiment described later.
  • the tail suspension test (Tail suspension test) is a test for measuring the struggling time of a mouse suspended upside down, and is generally one of the tests for evaluating depression-like behavior.
  • the suspended mouse moves about to escape, but the time it does not move (immobility time) gradually increases.
  • immobility time in mice treated with antidepressants.
  • a longer immobility time is interpreted as an increase in depression-like behavior, and a decrease in immobility time is interpreted as a decrease in depression-like behavior.
  • the short duration of inactivity can be interpreted as reflecting attention-deficit/hyperactivity disorder-like behavior, and the duration of inactivity can be used to test the effect on attention-deficit/hyperactivity disorder. it can.
  • the tail of the mouse was taped to a suspension bar in a suspension box made of Plastec having a height of 55 cm, a width of 60 cm and a depth of 11.5 cm.
  • the test time was 6 minutes, and the total immobility time in the last 4 minutes was measured.
  • Oxytocin, Compounds 2 and 5 were each dissolved in phosphate buffered saline (PBS) at a concentration of 100 ng/mL, and a single dose of 0.3 mL/mouse was intraperitoneally administered to CD38KOCC male mice. A group to which only PBS was administered was also prepared as a control. Subsequently, a microsuspension test was performed 30 minutes and 24 hours after the administration.
  • PBS phosphate buffered saline
  • FIG. 3 is a graph showing the results of the tail suspension test.
  • OT represents oxytocin
  • 2 represents compound 2
  • 5 represents compound 5.
  • the vertical axis represents the length of idle time (seconds).
  • * indicates that there is a significant difference at p ⁇ 0.05.
  • sucrose preference test The sucrose preference test is considered to reflect the depression state of human depression or Parkinson's disease and the apathy (unpleasant sensation) that is observed due to a decrease in the willingness to socialize (QOL), and indifference to others. There is. In mice that are overstressed, there is a behavioral change in which they no longer take the sucrose water that they originally prefer. It is also known that this reaction is improved by treatment with antidepressant drugs.
  • oxytocin, Compounds 2 and 5 were each dissolved in phosphate buffered saline (PBS) at a concentration of 100 ng/mL, and each was intraperitoneally administered once to each CD38KOCC male mouse at a dose of 0.3 mL/mouse. .. A group to which only PBS was administered was also prepared as a control.
  • PBS phosphate buffered saline
  • mice in each group were placed in a state where they could freely choose between water and 1% sucrose solution, and the consumption of water and sucrose solution was quantified 1 hour and 24 hours after administration. did.
  • FIGS. 4A and 4B are graphs showing the results of quantifying the consumption amounts of water and sucrose solution.
  • FIG. 4(a) is a graph showing the results 1 hour after the administration of each compound
  • FIG. 4(b) is a graph showing the results 24 hours after the administration of each compound.
  • “OT” represents oxytocin
  • “2” represents compound 2
  • “5” represents compound 5
  • the vertical axis represents the consumption of water or sucrose solution.
  • "*" indicates that there is a significant difference at p ⁇ 0.05.
  • FIGS. 5(a) to 5(c) are graphs showing the measurement results of plasma concentrations of oxytocin, compound 2 and compound 5 measured by the LC-MS/MS method.
  • 5A shows the measurement result of oxytocin
  • FIG. 5B shows the measurement result of compound 2
  • FIG. 5C shows the measurement result of compound 5.
  • the concentration of endogenous oxytocin was also measured at the same time.
  • OT indicates oxytocin
  • 2 indicates compound 2
  • 5 indicates compound 5.
  • the horizontal axis shows the time (minutes) after administration, and the vertical axis shows the plasma concentration (ng/mL) of each compound.
  • Table 4 shows the measurement results of pharmacokinetic parameters.
  • “Fast period” indicates that the calculation was performed based on the measured value 15 minutes after the administration of the compound
  • “Slow period” was calculated based on the measured value 15 to 60 minutes after the administration of the compound.
  • CSF indicates cerebrospinal fluid.
  • FIG. 6 is a graph showing the measurement results of the plasma concentration of each compound.
  • OT represents oxytocin
  • 2 represents compound 2
  • 5 represents compound 5.
  • the horizontal axis represents time (minutes) and the vertical axis represents the ratio (%) to the initial concentration.
  • the concentration of all compounds was within the range of 85 to 115% with respect to the initial concentration, and it was considered that they were stable even after incubation in plasma at 37°C for 2 hours.
  • This result indicates that the disappearance of oxytocin, Compound 2 and Compound 5 in blood is not due to decomposition by enzymatic digestion, but is due to clearance or adsorption to various tissues and organs.
  • a kinetic competition curve was measured for each of oxytocin, compound 2, and compound 5 at three concentrations (near Ki, 5-fold Ki, and 10-fold Ki). Specifically, 500 pM [ 3 H]oxytocin and various concentrations of competing compounds were added to the crude membrane fraction of HEK-293 cells forcibly expressing hOTR, and after incubation for various times, [ 3 H] The amount of oxytocin bound was measured. Non-specific binding was determined in the presence of 1 ⁇ M unlabeled oxytocin.
  • FIG. 7(a) to 7(c) are graphs showing measured exercise competition curves.
  • FIG. 7( a) shows the results for oxytocin
  • FIG. 7( b) shows the results for compound 2
  • FIG. 7( c) shows the results for compound 5.
  • Table 5 below shows the measurement results of reaction kinetic parameters of each compound.
  • Compound 2 showed a t 1/2 of about 1/2 that of [ 3 H]oxytocin. Moreover, the compound 2 showed t 1/2 of about 1/6 of the compound 5. Compound 5 also showed faster association and dissociation rates compared to [ 3 H]oxytocin.
  • FIG. 8 is a graph showing the measurement results of the uterine muscle contraction inducing effect of oxytocin, carbetocin, compound 2 and compound 5.
  • the horizontal axis represents the concentration of each compound
  • the vertical axis represents the ratio (%) with the spontaneous contraction value as 100%.
  • the EC 50 of Compound 2 was 55.5 pM, which was the same among natural oxytocin (238.8 pM), carbetosine (2.7 nM), Compound 1 (182.3 pM) and Compound 5 (3.1 nM). It became clear that it was the highest. Further, the EC 50 of Compound 3 was >10 nM and the EC 50 of Compound 6 was 8.1 nM.
  • a novel oxytocin derivative can be provided.

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PCT/JP2019/050089 2018-12-27 2019-12-20 オキシトシン誘導体及びその使用 WO2020137880A1 (ja)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56150050A (en) * 1980-03-24 1981-11-20 Ferring Ab Oxitocin derivative
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