WO2013029279A1 - Nouvel analogue de glp-1, son procédé de préparation et son utilisation - Google Patents

Nouvel analogue de glp-1, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2013029279A1
WO2013029279A1 PCT/CN2011/079307 CN2011079307W WO2013029279A1 WO 2013029279 A1 WO2013029279 A1 WO 2013029279A1 CN 2011079307 W CN2011079307 W CN 2011079307W WO 2013029279 A1 WO2013029279 A1 WO 2013029279A1
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Prior art keywords
glp
group
ala
lys
parent peptide
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PCT/CN2011/079307
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English (en)
Chinese (zh)
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姚志勇
李新宇
支钦
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深圳市健元医药科技有限公司
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Priority to PCT/CN2011/079307 priority Critical patent/WO2013029279A1/fr
Priority to CN201180038091.2A priority patent/CN103189389B/zh
Publication of WO2013029279A1 publication Critical patent/WO2013029279A1/fr

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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • the present invention relates to the field of medicinal chemistry and organic chemistry, and in particular to polypeptide analogs, to methods of preparing polypeptide analogs, compositions and their use in pharmacy.
  • Glucagon-like peptide-1 is a small intestine-L A polypeptide hormone secreted by a cell.
  • GLP-I is a 30 amino peptide fragment that is cleaved from a 160 amino acid proglucagon (PG) peptide chain.
  • GLP- I can promote insulin secretion, inhibit glucagon release, promote the expression of proinsulin gene and delay gastric emptying and gastric acid secretion at high blood sugar levels, and find GLP- I can increase satiety (suppress appetite) and reduce energy intake.
  • Long-term injection of GLP-I or exendin-4 (a long-acting analog of human GLP-I) can increase rat beta- The number of cell clusters.
  • GLP- regulates blood glucose levels through a variety of independent mechanisms of action, causing widespread concern in the prevention and treatment of diabetes.
  • L-cells in the gastrointestinal tract are regulated by blood glucose, secreting GLP-I peptide, with a half-life of 5 min and a metabolic clearance rate of 12-13 min.
  • GLP-I is degraded by DDP IV (dipeptidyl peptidase IV), ie, the N-terminal two amino acid residues are removed and converted into inactive GLP- I peptide. Due to the extremely short half-life reduction of GLP-I, its clinical application has been limited, and some analogs with GLP-I-like biological activity have been studied. Such as exendin-4 isolated from the saliva of snakes, It is highly homologous to the GLP-I sequence, has similar physiological effects, and has a longer half-life.
  • the N-terminal cleavage product exendin of E xendin-4 is capable of interacting with the GLP-I receptor on the surface of beta cells ( GLP-I-R) antagonizes and specifically inhibits GLP-I-mediated insulin secretion by duodenal glucose and oral nutrients.
  • GLP-I is molecularly engineered to resist enzyme degradation and enhance activity, including N-terminal The methylation, deamination, hydroxylation, etc. of the His free amino group, and the D2 type amino acid substitution of the second Ala have achieved the desired effect, possibly 2
  • the treatment of type 2 diabetes opens up new avenues.
  • Essexide ( exenatide ) from Lilly Corporation which is currently in clinical use , is the first novel GLP - I agonist injection .
  • Glycemic control for type 2 diabetes patients with metformin and sulfonylureas that control uncontrolled blood glucose has been marketed in the United States.
  • Conjuchem's CJC1131 is a stereoisomer of position 8 with a non-natural D-alanine GLP- I and a linker with a chemically active group, covalently bound to albumin after injection, with a half-life of about 10-12 h.
  • GLP-I N-glutamic acid -GLP-I and N-acetyl-GLP-I
  • GLP- Compared with I it has a long half-life and a strong insulin-promoting effect.
  • these drugs have strong side effects, which can cause side effects such as nausea and vomiting, and the steps of chemical synthesis are cumbersome and the price is very high.
  • GLP-I analogue Therefore, people are eager to develop a high activity, good stability, easy to use chemical synthesis, and fewer side effects can be used to treat diabetes. GLP-I analogue.
  • the object of the present invention is to develop a highly active GLP-I analogue for the treatment of diabetes and as a new generation of drugs for the treatment of diabetes.
  • the inventors have carried out a large number of experimental studies to modify the GLP-I molecule, and the results show that the GLP- The I analog has a longer half-life, has insulinotropic activity, has no clinical adverse effects, and can be used for the treatment of diseases such as diabetes, thereby completing the present invention.
  • a first aspect of the invention provides a GLP-I analog comprising a parent peptide of the following sequence:
  • R 1 -OH or -NH 2 ;
  • Xaa7 histidine, D-histidine, deamination-histidine, 2-amino-histidine, ⁇ -hydroxyl Histidine, homohistidine, N ⁇ -acetyl-histidine, ⁇ -fluoromethyl-histidine, ⁇ -methyl-histidine, 3-pyridyl alanine, 2-pyridyl Alanine or 4- Pyridyl alanine;
  • Xaa8 Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl) Carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid or (1-amino group) Cyclooctyl)carboxylic acid;
  • Xaa34 Lys, Glu, Asn or Arg,
  • Xaa37 Gly, Ala, Glu, Pro or Lys, and Xaa34 or Xaa37 At least one of them is Lys;
  • the GLP-I analog also contains Q1 and Q2 groups, and the Q1 and Q2 groups are simultaneously present in the parent peptide.
  • Xaa26, Xaa34, Xaa37 When any two or all of them are Lys, any two Lys in Xaa26, Xaa34, Xaa37 are linked in the form of an amide bond. Residue
  • the Q1 group is a lipophilic substituent attached to a bridging group W, and the lipophilic substituent forms an amide bond with the amino group of a bridging group at its carboxyl group, a carboxyl group of the amino acid residue of the bridging group and a parent peptide
  • An N-terminal residue of Lys forms an amide bond to be attached to the parent peptide
  • the bridging group W is 1-7 methylene-free branched paraffins ⁇ , ⁇ -dicarboxy
  • the lipophilic substituent is An acyl group selected from the group consisting of CH 3 (CH 2 ) n CO-, wherein n is an integer from 4 to 38 ;
  • each symbol is as follows, His : histidine, Ala: alanine, Glu: glutamic acid, Gln: Glutamine, Gly: glycine, Thr: threonine, Phe: phenylalanine, Ser: serine, Asp: aspartic acid, Val: proline , Tyr : Tyrosine , Leu : Leucine , Ile : Isoleucine , Lys : Lysine , Trp : Tryptophan , Arg : Arginine , Asn : Asparagine, Pro : Proline, Aib : 2-Aminoisobutyric acid, AEEA : 2-(2-(2-Aminoethoxy)ethoxy)acetic acid, MPA : 3- Maleimide propionic acid.
  • Xaa7 is preferably histidine.
  • Xaa8 is preferably D-Ala.
  • the bridging group W is preferably a non-branched alkane having 2 methylene groups, ⁇ - Dicarboxyl; further preferred is glutamic acid.
  • the lipophilic substituent is preferably CH 3 (CH 2 ) n CO , wherein n is an integer from 4 to 24; further preferably CH 3 (CH 2 ) 14 CO- .
  • the GLP-I analog of the present invention has insulinotropic activity, good stability, long half-life, and no clinical adverse effects.
  • Another aspect of the invention provides a method of preparing a GLP-I analog of the first aspect of the invention, comprising: synthesizing GLP- The parent peptide of the I analog, the free amino group and the free carboxyl group on the parent peptide are protected by a protecting group; the protecting group on the amino acid residue at the coupling position of the Q1 group at the parent peptide is removed, Q1 a group coupled to the parent peptide; a protecting group on the amino acid residue at the coupling position of the Q2 group on the parent peptide, Q2 The group is coupled to the parent peptide; the protecting group on the other amino acid residues on the parent peptide is removed, and the GLP-I analog is prepared.
  • the carboxyl group is generally protected in the form of a salt or an ester.
  • Commonly used salts are potassium salt, sodium salt, triethylamine salt, and tributylamine salt; commonly used esters have methyl esters ( OMe), ethyl ester (OEt), benzyl ester (oBzl), tert-butyl ester (OtBu).
  • Commonly used amino protecting groups are benzyloxycarbonyl (CBZ) and tert-butoxycarbonyl (Boc). ), p-toluenesulfonyl (Tosyl) and the like.
  • the method further comprises the step of: purifying the prepared GLP-I analog using reverse phase liquid chromatography.
  • GLP- I analog purification can be further purified using techniques well known in the art, such as molecular sieves, adsorption chromatography, affinity chromatography, hydrophobic chromatography, electrophoresis, concentrated crystallization, and the like.
  • the coupling of a Q1 group to the parent peptide comprises: The carboxyl group of the amino acid residue of the bridging group and the N- of the Lys of the parent peptide An amide bond is formed on the terminal residue to be attached to the parent peptide, and the lipophilic substituent is coupled to the parent peptide by an amide bond between the carboxyl group and the amino group of a bridging group.
  • the coupling of a Q2 group to the parent peptide comprises: MPA with its carboxyl group and one of the parent peptide An amide bond is formed on the N-terminal residue of Lys.
  • the preparation method of the GLP-I analog of the invention is simple, the product yield is high, and the preparation cost is greatly reduced.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the GLP- of the first aspect of the invention I analog or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises: 0.9 mg/ml of the GLP of the first aspect of the invention I analog or a pharmaceutically acceptable salt thereof, 5.0% (w/v) cresol, 5.2% (w/v) mannitol, 12.5 mg/ml propylene glycol, 8.0 mM Phosphate buffer.
  • the pH is usually from about 5 to 8, preferably from 6 to 8, more preferably from 7 to 7.5.
  • the GLP-I analog When the GLP-I analog is used in the preparation of a medicament, it is preferably a pharmaceutically acceptable salt thereof.
  • GLP- of the present invention The I analog can be reacted with any of the inorganic bases, inorganic and organic acids to form a salt.
  • the acid which is usually used to form an acid addition salt is an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and an organic acid such as p- Toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Preferred acid addition salts are those formed with mineral acids such as hydrochloric acid, hydrobromic acid, more preferably with hydrochloric acid.
  • the base addition salts include salts derived from inorganic base derivatives such as ammonium or alkali metal or rare earth metal hydroxides, carbonates, hydrogencarbonates and the like. Such bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate and the like.
  • compositions of the invention may also include pharmaceutically acceptable carriers thereof.
  • pharmaceutically acceptable carrier' refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
  • the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991) A full discussion of pharmaceutically acceptable excipients can be found.
  • Pharmaceutically acceptable carriers in the compositions can include liquids such as water, saline, glycerol and ethanol.
  • auxiliary substances such as disintegrants, wetting agents, emulsifiers, and the like may also be present in these carriers.
  • pH buffer material etc.
  • these materials can be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium wherein the pH is usually about 5-8, preferably, the pH is about 6-8. .
  • compositions of the present invention various dosage forms such as pills, tablets, capsules can be prepared using techniques well known in the art.
  • An injection or the like is preferably an injection.
  • the injection may be a solution type, a sterile powder, preferably a sterile powder.
  • the GLP-I analog of the present invention or a pharmaceutically acceptable salt thereof is used according to a technique well known in the art.
  • the solvent used is selected from the group consisting of water for injection, soybean oil for injection, ethanol, glycerin, propylene glycol, polyethylene glycol, benzyl benzoate, dimethylethanolamine.
  • Other substances such as Tween 80 can be added to the solution.
  • the solution can be selected from acetic acid - sodium acetate, citric acid - A sodium citrate, lactic acid, phosphate buffer system, preferably a phosphate buffer system.
  • the formulated solution is prepared as an injection after filtration to remove solid particles, remove heat, sterilize or sterilize, and if the injection is a sterile powder, it further includes freeze-drying, and these techniques are well known in the art.
  • the administration route of the injection of the present invention may be intravenous, spinal injection, intramuscular, subcutaneous or intradermal injection, preferably intravenous, intramuscular, subcutaneous, and more preferably intravenous, depending on medical needs.
  • the effective dose can vary depending on the severity of the subject to be administered or treated. The specific situation depends on the individual circumstances of the subject (such as the subject's weight, age, physical condition, and the desired effect) It is decided that this is within the scope of the skilled physician.
  • compositions of the present invention are stable, and vascular irritation, muscle irritation, allergic and hemolysis experiments demonstrate no adverse clinical response.
  • Another aspect of the invention is the use of a GLP-I analogue of the invention in the manufacture of a medicament for the treatment or prevention of a disease.
  • These diseases include hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, X Syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, indigestion or gastric ulcer.
  • the GLP-I analog is for use in the manufacture of a medicament for delaying or preventing the development of type 2 diabetes.
  • the GLP-I analog of the invention reduces food intake, reduces beta-cell apoptosis, and enhances beta-preparation Use of cell function and beta-cell mass and/or recovery of beta-cell glucose sensitivity in drugs.
  • the peptide resin obtained in 1a) was added to chloroform, Pd(PPh 3 ) 4 , NMM was added under argon atmosphere, and the reaction was stirred for 2 hours. After washing with DMF and DCM, the resin was added to Fmoc-Glu-Otbu, DIC, HOBt. NMP mixed solution, coupled for 2 hours, piperidine / DMF to remove Fmoc group, add palmitic acid, DIC, HOBt NMP coupling solution, coupled for 3 hours, get: Boc-His (Boc)-D-Ala-Glu(Otbu)-Gly-Thr(tbu)-Phe-Thr
  • NMP DCM is 1:1 (volume ratio) solution will be 1b
  • the resulting protected peptidyl resin was washed twice, freshly prepared 2% hydrazine NMP solution was added, and the reaction mixture was shaken at room temperature for 12 minutes and then filtered. Repeat the ⁇ processing step twice. After that NMP, DCM and NMP wash the resin thoroughly. Add Fmoc-AEEA-OH, HBTU, DIEA NMP mixed coupling solution, shake 3 After the hour, the mixture was filtered, washed, and the Fmoc group was removed by piperidine/DMF.
  • the crude product obtained in 1d) was dissolved in 5% acetic acid / H 2 O and purified by two semi-preparative HPLC on a 10 ⁇ m reversed C18 packed 50 mm x 250 mm column.
  • the column was eluted with a gradient of 32-50% CH 3 CN-0.1% TFA/H 2 O at 50 ml/min for 45 minutes, and the peptide-containing fraction was collected, concentrated to remove CH 3 CN, and then lyophilized.
  • the isolated product was analyzed by PDMS and the m/z value of the protonated molecular ion peak was found to be 4106.31 ⁇ 3 .
  • the molecular weight of Compound 1 prepared in Example 1 was found to be 4105.31 ⁇ 3 Da (theoretical value 4105.31).
  • Staphylococcus aureus V8 The target compound is subjected to enzymatic cleavage, followed by mass spectrometry of the peptide fragment by PDMS to determine the acylation position (Lys26, Lys37).
  • Example 1 The compounds prepared in Example 1 were examined from three experiments: pharmacokinetics, in vitro activity assay, and pharmacodynamic analysis. Animal experiments, the results are as follows:
  • IV intravenous injection
  • SC subcutaneous injection
  • the compound 1 and GLP-I prepared in Example 1 were separately administered.
  • the animals were bled at different times within 0-360 hours after dosing, and the plasma of each sample was collected and used with N- End-specific radioimmunoassay analysis.
  • Calculate pharmacokinetic parameters using model-dependent (data for IV) and model-independent (for SC-derived data) data as shown in Table 1-1 and Table 1-2 is shown.
  • the elimination half-life of Compound 1 administered by IV was approximately 19 hours, and the elimination half-life of GLP-I was approximately 12 hours.
  • Compound 1 has an elimination half-life of approximately 15 hours and a GLP-I elimination half-life of approximately 8 hours.
  • Compound 1 and GLP-I were administered by IV or SC route , no clinical adverse hair should occur. From Table 1-1 and Table 1-2, it can be observed that Compound 1 prolongs the elimination half-life, reduces the clearance rate, and the like.
  • C max represents the maximum observed plasma concentration
  • T max represents the time at which the observed maximum plasma concentration is reached
  • AUC 0-last represents the area under the plasma concentration-time curve measured from 0 to infinity
  • 1/2 represents the elimination half-life in hours
  • CL/F represents the total body clearance as a function of bioavailability
  • Vss/F represents the volume of distribution at steady state as a function of bioavailability.
  • HEK-293 cells stably expressing the human GLP-I receptor for the CRE-luciferase system, per well 120 ⁇ l Low serum DMEM FBS medium, 30,000 cells were seeded into 96-well plates. On the second day after inoculation, a 20 ⁇ l aliquot of the sample to be tested was dissolved in 0.5% BSA. Medium, mixed with the cells and incubated for 5 hours.
  • the preparation of the test compound 1 is from 0.001 nM to 15 dilutions of 10nM for 15 samples of GLP-I from 0.001nM to 10nM and Val8-GLP-I (7-37) OH Standards Prepare 10 standard solutions of 0.3nM and 3nM. After incubation, add 100 ⁇ l of luciferase reagent directly to each plate and mix gently 2 Minutes. The plate was placed in a Tri-lux luminometer and the light output due to luciferase expression was calculated.
  • the average EC50 values for Compound 1 and GLP-I are as follows: Average for Compound 1 The EC50 values were 0.42 ⁇ 0.05 nM and the average EC50 of GLP-I was 0.28 ⁇ 0.04 nM.
  • Compound 1 and GLP- I were administered by subcutaneous injection (SC) according to 0.01 mg/kg, respectively.
  • the dose is administered to male cynomolgus monkeys.
  • the control solution phosphate buffer was also injected by a subcutaneous injection (SC) route at a dose of 0.01 mg/kg.
  • Subcutaneous injection of 0.01mg/kg dose of compound After 1 and GLP-I, glucose solution was infused step by step on 1, 2, 3, 5, 7, and 10 days.
  • Subcutaneous injection (SC) 0.01mg/kg Immediately after the injection of the control solution, the glucose solution was infused stepwise. The stepwise infusion of glucose solution was performed on monkeys given sedatives after fasting for 15 hours.
  • the peptide resin obtained in 1a) was added to chloroform, Pd(PPh 3 ) 4 , NMM was added under argon atmosphere, and the reaction was stirred for 2 hours.
  • the resin was washed with DMF, DCM, and then added with Fmoc-Glu-OtBu, DIC, HOBt.
  • NMP coupling solution coupled for 3 hours, piperidine / DMF to remove Fmoc group, add palmitic acid, DIC, HOBt, NMP coupling solution, coupled for 3 hours, get: Boc -His(Boc)-D-Ala-Glu(Otbu)-Gly-Thr(tbu)-Phe-Thr(tbu)
  • the crude product obtained in 1d) was dissolved in 5% acetic acid / H 2 O and purified by two semi-preparative HPLC on a 10 ⁇ m reverse phase C18 packed 50 mm x 250 mm column.
  • the column was eluted with a gradient of 34-46% CH3CN-0.1% TFA/H 2 O at 50 ml/min for 45 minutes, and the peptide-containing fraction was collected, concentrated to remove CH 3 CN, and then lyophilized.
  • the separated product was analyzed by PDMS and the m/z value of the protonated molecular ion peak was found to be 3949.31 ⁇ 3 .
  • the molecular weight of the compound 2 prepared in Example 2 was found to be 3948.31 ⁇ 3 Da (theoretical value: 3948.31).
  • Example 2 The compounds prepared in Example 2 were examined from three experiments of pharmacokinetics, in vitro activity assay, and pharmacodynamic analysis. Animal experiments, the results are as follows:
  • IV intravenous injection
  • SC subcutaneous injection
  • the compound 2 and GLP-I prepared in Example 2 were separately administered.
  • the animals were bled at different times within 0-360 hours after dosing, and the plasma of each sample was collected and used with N- End-specific radioimmunoassay analysis.
  • Calculate pharmacokinetic parameters using model-dependent (data for IV) and model-independent (for SC-derived data) data as shown in Table 2-1 and Table 2-2 is shown.
  • the elimination half-life of Compound 2 administered by IV is approximately 23 hours
  • the elimination half-life of GLP-I is approximately 12 hours.
  • C max represents the maximum observed plasma concentration
  • T max represents the time at which the observed maximum plasma concentration is reached
  • AUC 0-last represents the area under the plasma concentration-time curve measured from 0 to infinity
  • 1/2 represents the elimination half-life in hours
  • CL/F represents the total body clearance as a function of bioavailability
  • Vss/F represents the volume of distribution at steady state as a function of bioavailability.
  • HEK-293 cells stably expressing the human GLP-I receptor for the CRE-luciferase system, per well 120 ⁇ l of low serum DMEM FBS medium and 30,000 cells were seeded into 96-well plates. On the second day after inoculation, dissolve the 20 ⁇ l aliquot of the sample to be tested. In 0.5% BSA, mix with the cells and incubate for 5 hours.
  • the preparation of the test compound 1 contains 15 dilutions from 0.001nM to 10nM, 15 dilutions from 0.001nM to 10nM for GLP-I to be tested, and Val8- The GLP-I (7-37) OH standard was prepared in 10 standard solutions of 0.3 nM and 3 nM. After incubation, 100 ⁇ l Luciferase reagent was added directly to each plate and gently mixed for 2 minutes. The plate was placed in a Tri-lux luminometer and the light output due to luciferase expression was calculated. Average of compound 2 and GLP-I The EC50 values were as follows: Compound 2 had an average EC50 of 0.44 ⁇ 0.06 nM; GLP-I had an average EC50 of 0.28 ⁇ 0.04 nM. .
  • Compound 2 and GLP- I were administered by subcutaneous injection (SC) according to 0.01 mg/kg The dose is administered to male cynomolgus monkeys.
  • the control solution phosphate buffer was also injected by a subcutaneous injection (SC) route at a dose of 0.01 mg/kg.
  • Subcutaneous injection (SC) 0.01mg/kg Immediately after the injection of the control solution, the glucose solution was infused stepwise. The stepwise infusion of glucose solution was performed on monkeys given sedatives after fasting for 15 hours. At the beginning of the infusion of glucose solution 10 A minute before the blood sample is taken to define the baseline. Then, re-infusion for 30 minutes at a rate of 15 mg/kg/min. During the infusion, to 15 Blood samples were taken at intervals and insulin levels were determined by immunoassay. The data are shown in Tables 2-3 and
  • NMP DCM is 1:1 (volume ratio) solution will be 1b
  • the resulting protected peptidyl resin was washed twice, freshly prepared 2% hydrazine NMP solution was added, and the reaction mixture was shaken at room temperature for 12 minutes and then filtered. Repeat the ⁇ processing step twice. After that NMP, DCM and NMP wash the resin thoroughly. Add Fmoc-AEEA-AEEA-OH, HBTU, DIEA NMP mixed coupling solution, shake 3 After the hour, the mixture was filtered, washed, and the Fmoc group was removed by piperidine/DMF.
  • the crude product obtained in 1d) was dissolved in 5% acetic acid / H 2 O and purified by two semi-preparative HPLC on a 10 ⁇ m reverse phase C8 packed 50 mm x 250 mm column.
  • the column was eluted with 35-54% CH3CN-0.1% TFA / H 2 O gradient at 50ml / min 45 minutes to collect the fraction containing the peptide, was concentrated to remove CH3CN after lyophilization.
  • the isolated product was analyzed by PDMS and the m/z value of the protonated molecular ion peak was found to be 4205.78 ⁇ 3 .
  • the molecular weight of Compound 3 prepared in Example 3 was found to be 4204.78 ⁇ 3 Da (theoretical value 4204.78).
  • Staphylococcus aureus V8 The target compound is subjected to enzymatic cleavage, followed by mass spectrometry of the peptide fragment by PDMS to determine the acylation position (Lys26, Lys34).
  • Example 3 The compounds prepared in Example 3 were examined from three experiments of pharmacokinetics, in vitro activity assay, and pharmacodynamic analysis. Animal experiments, the results are as follows:
  • IV intravenous injection
  • SC subcutaneous injection
  • the compound 3 and GLP-I prepared in Example 3 were separately administered.
  • the animals were bled at different times within 0-360 hours after dosing, and the plasma of each sample was collected and used with N- End-specific radioimmunoassay analysis.
  • Calculate pharmacokinetic parameters using model-dependent (data for IV) and model-independent (for SC-derived data) data as shown in Table 3-1 and Table 3-2 is shown.
  • the elimination half-life of Compound 3 administered by IV is approximately 16 hours
  • the elimination half-life of GLP-I is approximately 12 hours.
  • Cmax represents the maximum observed plasma concentration
  • Tmax represents the time at which the observed maximum plasma concentration is observed
  • AUC0-last represents the measured plasma concentration from 0 to infinity - the area under the time curve
  • T 1/2 represents the elimination half-life in hours
  • CL/F Indicates the total body clearance as a function of bioavailability
  • Vss/F represents the volume of distribution at steady state as a function of bioavailability.
  • HEK-293 cells stably expressing human GLP-I receptor for CRE-luciferase system, per well 120 ⁇ l of low serum DMEM FBS medium and 30,000 cells were seeded into 96-well plates. On the second day after inoculation, dissolve the 20 ⁇ l aliquot of the sample to be tested. In 0.5% BSA, mix with the cells and incubate for 5 hours.
  • the test compound 3 is prepared to contain 15 dilutions from 0.001nM to 10nM for 15 dilutions from 0.001nM to 10nM for the GLP-I to be tested, and Val8- The GLP-I (7-37) OH standard was prepared in 10 standard solutions of 0.3 nM and 3 nM. After incubation, 100 ⁇ l Luciferase reagent was added directly to each plate and gently mixed for 2 minutes. The plate was placed in a Tri-lux luminometer and the light output due to luciferase expression was calculated. Average of compound 3 and GLP-I The EC50 values were as follows: Compound 3 had an average EC50 of 0.33 ⁇ 0.06 nM; GLP-I had an average EC50 of 0.28 ⁇ 0.04 nM. .
  • Compound 3 and GLP-I were administered by subcutaneous injection (SC) according to 0.01 mg/kg, respectively.
  • the dose is administered to male cynomolgus monkeys.
  • the control solution phosphate buffer was also injected by a subcutaneous injection (SC) route at a dose of 0.01 mg/kg.
  • Subcutaneous injection of 0.01 mg/kg of compound 3 After GLP-I, the glucose solution was infused in steps of 1, 2, 3, 5, 7, and 10 days.
  • Subcutaneous injection (SC) 0.01mg/kg Immediately after the injection of the control solution, the glucose solution was infused stepwise. The stepwise infusion of glucose solution was performed on monkeys given sedatives after fasting for 15 hours. At the beginning of the infusion of glucose solution 10 A minute before the blood sample is taken to define the baseline. Then, re-infusion for 30 minutes at a rate of 15 mg/kg/min. During the infusion, to 15 Blood samples were taken at intervals and insulin levels were determined by immunoassay. The data are shown in
  • Table 3-3 Average value of compound 3 ( ⁇ SD) Pharmacodynamic parameter value Area under the insulin curve Injection AUC 0-last (pM*min) Day 1 Day 2 Day 3 Day 5 Day 7 Day 10 average value SD average value SD average value SD average value SD average value SD average value SD average value SD average value SD Control solution 15432 3529 14251 2234 14012 2014 13984 1819 12759 1587 11845 1096 Compound 3 32996 2981 30121 1854 26731 1843 20454 1312 15342 1534 11131 832
  • Table 3-4 Average value of GLP-I ( ⁇ SD) Pharmacodynamic parameter value Area under the insulin curve Injection AUC 0-last (pM*min) Day 1 Day 2 Day 3 Day 5 Day 7 Day 10 average value SD average value SD average value SD average value SD average value SD average value SD average value SD average value SD Control solution 15432 3529 14251 2234 14012 2014 13984 1819 12759 1587 11845 1096 GLP- I 31254 3542 30045 2432 21123 1563 15542 1348 11764 1141 10548 1248
  • the peptide resin obtained in 1a) was added to chloroform, Pd(PPh 3 ) 4 , NMM was added under argon atmosphere, and the reaction was stirred for 2 hours.
  • the resin was washed with DMF, DCM, and then added with Fmoc-Glu-OtBu, DIC, HOBt.
  • NMP coupling solution coupled for 3 hours, piperidine / DMF to remove Fmoc group, add palmitic acid, DIC, HOBt, NMP coupling solution, coupled for 3 hours, get: Boc -His(Boc)-D-Ala-Glu(Otbu)-Gly-Thr(tbu)-Phe-Thr(tbu)-
  • the separated product was analyzed by PDMS and the m/z value of the protonated molecular ion peak was found to be 4,097.65 ⁇ 3 . Therefore, the molecular weight of the compound 4 prepared in Example 4 was found to be 4096.65 ⁇ 3 Da (theoretical value 4096.65).
  • Staphylococcus aureus V8 The target compound is subjected to enzymatic cleavage, and then the mass of the peptide fragment is determined by PDMS to determine the acylation position (Lys26, Lys34, Lys37).
  • Example 4 The compounds prepared in Example 4 were examined from three experiments: pharmacokinetics, in vitro activity assay, and pharmacodynamic analysis. Animal experiments, the results are as follows:
  • IV intravenous injection
  • SC subcutaneous injection
  • the compounds prepared in Example 4 were separately administered with GLP-I.
  • the animals were bled at different times within 0-360 hours after dosing, and the plasma of each sample was collected and used with N- End-specific radioimmunoassay analysis.
  • Calculate pharmacokinetic parameters using model-dependent (data from IV) and model-independent (data from SC), as shown in Table 4-1 and Table 4-2 is shown.
  • the elimination half-life of Compound 4 administered by IV is approximately 18 hours, and the elimination half-life of GLP-I is approximately 12 hours.
  • C max represents the maximum observed plasma concentration
  • T max represents the time at which the observed maximum plasma concentration is reached
  • AUC 0-last represents the area under the plasma concentration-time curve measured from 0 to infinity
  • 1/2 represents the elimination half-life in hours
  • CL/F represents the total body clearance as a function of bioavailability
  • Vss/F represents the volume of distribution at steady state as a function of bioavailability.
  • HEK-293 cells stably expressing human GLP-I receptor for CRE-luciferase system were inoculated into 96-well plates according to 120 ⁇ l of low serum DMEM FBS medium per well and 30,000 cells per well. On the second day after inoculation, a 20 ⁇ l aliquot of the test sample was dissolved in 0.5% BSA, mixed with the cells and incubated for 5 hours.
  • Compound 4 and GLP- I were administered by subcutaneous injection (SC) according to 0.01 mg/kg The dose is administered to male cynomolgus monkeys.
  • the control solution phosphate buffer was also injected by a subcutaneous injection (SC) route at a dose of 0.01 mg/kg.
  • Subcutaneous injection of 0.01mg/kg dose of compound After 4 and GLP-I, glucose solution was infused in steps of 1, 2, 3, 5, 7, and 10 days.
  • Subcutaneous injection (SC) 0.01mg/kg Immediately after the injection of the control solution, the glucose solution was infused stepwise. The stepwise infusion of glucose solution was performed on monkeys given sedatives after fasting for 15 hours. At the beginning of the infusion of glucose solution 10 A minute before the blood sample is taken to define the baseline. Then, re-infusion for 30 minutes at a rate of 15 mg/kg/min. During the infusion, to 15 Blood samples were taken at intervals and insulin levels were determined by immunoassay. The data are shown in Tables 4
  • Table 4-3 Average value of compound 4 ( ⁇ SD) Pharmacodynamic parameter value Area under the insulin curve Injection AUC 0-last (pM*min) Day 1 Day 2 Day 3 Day 5 Day 7 Day 10 average value SD average value SD average value SD average value SD average value SD average value SD average value SD average value SD average value SD Control solution 15432 3529 14251 2234 14012 2014 13984 1819 12759 1587 11845 1096 Compound 4 31953 2982 30123 1862 25728 1382 23449 1162 20632 1034 15121 990
  • Table 4-4 Average value of GLP-I ( ⁇ SD) Pharmacodynamic parameter value Area under the insulin curve Injection AUC 0-last (pM*min) Day 1 Day 2 Day 3 Day 5 Day 7 Day 10 average value SD average value SD average value SD average value SD average value SD average value SD average value SD average value SD Control solution 15432 3529 14251 2234 14012 2014 13984 1819 12759 1587 11845 1096 GLP- I 31254 3542 30045 2432 21123 1563 15542 1348 11764 1141 10548 1248
  • Composition Formulation Compound 1 prepared in Example 1 at a concentration of 0.9 mg/ml at a concentration of 8.0 mM Phosphate buffer, 5.0% (w/v) cresol, 5.2% (w/v) mannitol, 12.5 mg/ml propylene glycol, pH about 7.5 .
  • the preparation process was as follows: 0.9 g of the compound prepared in Example 1 was added to a 100 00 beaker. g mannitol, 50g cresol, 12.5g propylene glycol, 750ml water, add phosphate to a concentration of 8 mM, and adjust the pH to 7.5 with 1N NaOH , add water for injection to volume. Before filtration, 12.5 g of activated carbon was added to the injection, and the pyrogen was adsorbed for 30 minutes while stirring, and decarburized and filtered. The filtrate was filtered through a 0.22 ⁇ m titanium rod filter and passed through 0.22 ⁇ m microporous membrane was sterilized and filtered. Each vial was filled into a 10 ml glass vial in an amount of 1.25 ml, lyophilized, plugged, and capped to obtain the compound prepared in Example 1 Formulation.
  • Example 5 Preparation of Example 5 from Example 5 The stability of the branch and the accelerated test were investigated. Local irritation was examined by animal vascular irritation, muscle irritation, hemolysis, and allergic experiments.
  • Example 5 A batch of samples prepared in Example 5 was placed at a temperature of 40 ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%. In the constant temperature and humidity chamber, the samples were taken at 0, 1, 2, 3 and 6 months, and the results are shown in Table 5-1.
  • Example 5 The results showed that the stimulation of the injection of Example 5 in the rabbit ear vein was 5%, and 5% There was no significant difference in glucose injection.
  • Visual observation showed no inflammatory reaction such as vascular congestion and surrounding tissue edema.
  • Tissue biopsy showed no abnormalities in vascular structure, endothelial damage, thrombosis, and other pathological changes.
  • the cumulative scores of blood vessels and surrounding tissues observed by the naked eye and light microscope are less than 0.5, indicating no irritation.
  • Example 5 Injection 1ml On the right side, the same volume of normal saline was injected. After the injection, observe the muscles at the injection site for congestion, edema, etc., half of the animals after 48 hours (day 3) The blood was sacrificed, the skin was cut longitudinally, and the injection sites on both sides of the injection were observed with or without hyperemia and edema, and the tissues were taken for pathological examination. Then evaluate the stimulatory response of the drug according to the criteria in Table 1-3. The remaining animals continue to observe 14d The above operation was repeated after the bloodletting was performed on the 18th day, and the evaluation criteria are shown in Table 5-3.
  • Level 1 Mild hyperemia at the site of administration, less than 0.15 cm in diameter level 2 Moderately hyperemia at the site of administration, diameter 0.15 to 1.0 cm
  • Level 3 Severe congestion, redness, and muscle degeneration at the site of administration level 4 Muscle brown degeneration, necrosis
  • Level 5 Severe muscle degeneration, large area necrosis
  • Example 5 Six healthy guinea pigs were selected, and 0.5 ml of the injection of Example 5 was injected intraperitoneally, and once every other day, a total of 3 injections were given. Times. Then, they were randomly divided into 2 groups, and 1 ml of the injection of Example 5 was intravenously administered 14 or 21 days after the first administration. Observe the guinea pig with allergies such as excitement and difficulty in breathing.
  • a 2% rabbit red blood cell suspension was prepared. Take 7 tubes and add various liquids according to Table 5-4. Gently shake each tube and set it 37 Incubate in a constant temperature water bath at °C and observe the results for 0.5, 1, 2, 3, and 6 hours. The criteria for judging agglutination and hemolysis of erythrocytes are shown in Table 5-5.

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Abstract

La présente invention concerne un analogue de peptide 1 de type glucagon (GLP-1) comprenant un peptide parent possédant la séquence d'acides aminés de GLP-1 (7-37) et deux groupes de modification couplés aux groupes amines de deux résidus de lysine du peptide parent par l'intermédiaire de liaisons amides, un des groupes comprenant un groupe maléimide (MPA). L'analogue de GLP-1 possède l'activité de l'insuline, une demi-vie longue et une bonne stabilité et induit moins d'effets secondaires, ce qui permet de l'utiliser pour traiter des maladies telles que le diabète. L'invention concerne également un procédé de synthèse, une composition et une utilisation pharmaceutique de l'analogue de GLP-1.
PCT/CN2011/079307 2011-09-03 2011-09-03 Nouvel analogue de glp-1, son procédé de préparation et son utilisation WO2013029279A1 (fr)

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US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
CN109369798A (zh) * 2018-12-25 2019-02-22 苏州天马医药集团天吉生物制药有限公司 一种合成索玛鲁肽的方法
CN110317258A (zh) * 2018-03-29 2019-10-11 齐鲁制药有限公司 一种索玛鲁肽的新多肽片段及其制备方法
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
CN111718407A (zh) * 2020-08-14 2020-09-29 北京质肽生物医药科技有限公司 一种胰高血糖素样肽-1类似物的纯化方法
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate

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EP3762408A1 (fr) * 2018-03-09 2021-01-13 Enzypep B.V. Synthèse chimio-enzymatique de semaglutide, de liraglutide et de glp-1
CN116410297A (zh) * 2021-07-19 2023-07-11 内蒙古博睿精创科技有限公司 长效glp-1多肽类似物及其制备方法和应用

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CN1350548A (zh) * 1999-05-17 2002-05-22 康久化学公司 长效促胰岛肽

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CN1232470A (zh) * 1996-08-30 1999-10-20 诺沃挪第克公司 Glp－1衍生物
CN1350548A (zh) * 1999-05-17 2002-05-22 康久化学公司 长效促胰岛肽

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
CN110317258A (zh) * 2018-03-29 2019-10-11 齐鲁制药有限公司 一种索玛鲁肽的新多肽片段及其制备方法
CN110317258B (zh) * 2018-03-29 2023-03-17 齐鲁制药有限公司 一种索玛鲁肽的新多肽片段及其制备方法
CN109369798A (zh) * 2018-12-25 2019-02-22 苏州天马医药集团天吉生物制药有限公司 一种合成索玛鲁肽的方法
CN111718407A (zh) * 2020-08-14 2020-09-29 北京质肽生物医药科技有限公司 一种胰高血糖素样肽-1类似物的纯化方法

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