WO2022111370A1 - Double agoniste du récepteur glp-1/glucagon et son application - Google Patents

Double agoniste du récepteur glp-1/glucagon et son application Download PDF

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WO2022111370A1
WO2022111370A1 PCT/CN2021/131369 CN2021131369W WO2022111370A1 WO 2022111370 A1 WO2022111370 A1 WO 2022111370A1 CN 2021131369 W CN2021131369 W CN 2021131369W WO 2022111370 A1 WO2022111370 A1 WO 2022111370A1
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gly
pro
lys
asp
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韩京
孟庆华
杨启萌
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江苏师范大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to biomedicine, in particular to a class of GLP-1/glucagon receptor dual agonists and applications thereof.
  • T2DM type 2 diabetes mellitus
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • dyslipidemia The incidence and course of the disease are closely related to obesity. Studies have shown that 80-90% of T2DM patients are clinically overweight or obese.
  • the use of weight loss therapy is beneficial to prevent and control the disease, including controlling blood sugar, reducing morbidity and disability (death) rates. It is generally difficult to achieve ideal weight loss through exercise and diet control alone.
  • the body's energy and blood sugar regulation signaling system includes a variety of different polypeptides.
  • Endogenous gastrointestinal hormones proglucagon (proglucagon) is a 160 amino acid precursor polypeptide, which is cleaved in different tissues. Converted into different products, such as GLP-1, glucagon-like peptide-2 (GLP-2), glucagon (Glucagon, GCG) and oxyntomodulin (Oxyntomodulin, OXM) and other endogenous gastric gut hormones.
  • GLP-1 glucagon-like peptide-2
  • Glucagon Glucagon
  • GCG glucagon
  • Oxyntomodulin oxyntomodulin
  • GLP-1 is a glucose-dependent hypoglycemic polypeptide hormone secreted by L cells in the terminal jejunum, ileum and colon, and exerts a hypoglycemic effect after specifically binding to the GLP-1 receptor.
  • the main advantage of GLP-1 is its glucose-dependent incretin secretion, which avoids the risk of hypoglycemia that is often present in the treatment of diabetes.
  • GLP-1 can also prevent pancreatic ⁇ -cell degeneration, stimulate ⁇ -cell proliferation and differentiation, and improve diabetes progression at the source.
  • GLP-1 also has the effects of inhibiting gastric acid secretion, delaying gastric emptying, and suppressing appetite, and has partial weight loss effects.
  • GLP-1 drugs such as liraglutide, semaglutide and dulaglutide.
  • GLP-1 drugs have a safe hypoglycemic effect, if you need to achieve better weight loss effect, it is generally necessary to increase the dosage, and large doses of GLP-1 drugs are prone to gastrointestinal side effects, which are tolerated The poor performance results in a narrow therapeutic window. Therefore, there remains a need for safer and more tolerated therapeutic agents that are effective for weight loss and glycemic control.
  • GCG is a hormone produced in the alpha cells of the pancreas. It acts on the liver under stress conditions such as cold and starvation, and decomposes glycogen in the liver to increase blood sugar.
  • GCG In addition to its blood sugar-raising effect, GCG also has the effect of promoting lipolysis, fat oxidation, and fever in the body (Diabetologia, 2017, 60, 1851–1861). However, these beneficial effects of GCG on energy metabolism have not been applied due to its inherent hypoglycemic effect.
  • OXM is an endogenous GLP-1 receptor and GCG receptor dual agonist in the human body, and its agonistic activity on GLP-1 receptor and GCG receptor is weaker than the natural ligand of each receptor (natural GLP). -1 or GCG).
  • the acute physiological effects of OXM include inhibition of gastric emptying, food intake and exocrine secretion of the stomach and pancreas, enhancement of resting energy expenditure, etc., resulting in weight loss.
  • intraperipheral administration of OXM in animals and humans reduces body weight and food intake, and in obese subjects increases metabolic rate and activity-related energy expenditure.
  • large doses of OXM are less prone to common gastrointestinal side effects such as nausea and vomiting while reducing body weight.
  • the reported polypeptide GLP-1/GCG receptor dual agonists can be divided into four categories based on GCG, OXM, GLP-1 or exendin-4 (exendin-4) according to their sequence structure. ⁇ :CN201911103118.6 ⁇ CN201780013643.1 ⁇ CN201680021972.6 ⁇ CN201580030150.X ⁇ CN201380048137.8 ⁇ WO2008/071972 ⁇ WO 2008/101017 ⁇ WO 2009/155258 ⁇ WO 2010/096052 ⁇ WO 2010/096142 ⁇ WO2011/ 075393, WO 2008/152403, WO 2010/070251, WO 2010/070252, WO 2010/070253, WO2010/070255, WO 2011/160630, WO 2011/006497, WO 2011/0876171, WO2111/08 WO2011/117416, WO 2012/177443, WO 2012/177444, WO 2012/150503, WO2013/004983, WO 2013/092703, WO 2014/041195 and WO 2014/041375
  • GLP-1/GCG/GIP receptor triple agonists that activate not only the GLP-1 receptor and GCG receptor, but also the glucose-dependent insulinotropic polypeptide (GIP) receptor.
  • GIP glucose-dependent insulinotropic polypeptide
  • XenGLP-1 is a class of animal-derived GLP-1 analogs found in Xenopus laevis. Compared with natural GLP-1, XenGLP-1 has better hypoglycemic activity and stability. Furthermore, in addition to being more resistant to degradation by dipeptidyl peptidase (DPP-IV) compared to GLP-1, OXM and GCG, XenGLP-1 also showed stable degradation against neutral endopeptidase (NEP). many.
  • DPP-IV dipeptidyl peptidase
  • NEP neutral endopeptidase
  • XenGLP-1 is a potent agonist of the GLP-1 receptor, however it does not activate the GCG receptor.
  • XenGLP-1 has many of the glucose-regulating effects observed with native GLP-1, and many preclinical studies have shown that XenGLP-1 has several beneficial antidiabetic properties, including glucose-dependent enhancement of insulin synthesis and secretion, slowed gastric emptying , food intake and weight loss, as well as promoting ⁇ -cell proliferation and restoring islet function, etc. (Biochem. Pharmacol., 2017, 142, 155-167; FASEB J., 2019, 33, 7113-7125). These effects are beneficial not only for diabetics, but also for patients suffering from obesity. Patients with obesity have a higher risk of developing hypertension, hyperlipidemia, diabetes, NAFLD, NASH, musculoskeletal and cardiovascular disease.
  • the object of the present invention is to provide a novel polypeptide compound with dual agonistic effect of GLP-1/GCG receptor, the polypeptide is a variant designed based on the sequence of XenGLP-1, which retains the therapeutic effect of XenGLP-1 on diabetes while having The beneficial effects of GCG on lipid metabolism and energy metabolism, resulting in synergistic effects on sugar, lipid, and energy metabolism, are more useful than single receptor agonists in the preparation of drugs for the treatment of metabolic syndrome, such as obesity, diabetes, NAFLD, NASH and other diseases more potential.
  • a class of GLP-1/GCG receptor dual agonist polypeptide compounds the general amino acid sequence formula of this class of GLP-1 receptor/GCG receptor dual agonist polypeptide compounds is:
  • Xaa 1 is taken from Ser, D-Ser or Aib;
  • Xaa 2 is taken from Glu or Gln;
  • Xaa 3 is taken from Thr or Ser
  • Xaa 4 is taken from Glu, Lys or Lys whose side chain is modified;
  • Xaa 5 is taken from Leu, Lys or Lys whose side chain is modified;
  • Xaa 6 is taken from Glu or Asp
  • Xaa 7 is taken from Glu or Ser
  • Xaa 8 is taken from Glu or Arg
  • Xaa 9 is taken from Ala or Arg
  • Xaa 11 is taken from Glu or Asp
  • Xaa 12 taken from Ile or Lys
  • Xaa 15 is taken from -NH 2 or Lys whose side chain is modified;
  • the Lys in which the side chain is modified is selected from Lys( ⁇ -Glu-CO-(CH 2 ) n -CH 3 ) or Lys(AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) n -COOH),
  • Lys( ⁇ -Glu-CO-(CH 2 ) n -CH 3 ) The structural formula of Lys( ⁇ -Glu-CO-(CH 2 ) n -CH 3 ) is shown below:
  • n is a natural number, and 12 ⁇ n ⁇ 20.
  • the n is 14, 16, 18 or 20.
  • amino acid sequence of the polypeptide compound is one of the following sequences:
  • the present invention also provides pharmaceutically acceptable salts of a class of GLP-1/GCG receptor dual agonist polypeptide compounds.
  • the salt is a salt formed by a GLP-1/GCG receptor dual agonist polypeptide compound and one of the following compounds: hydrobromic acid, hydrochloric acid, methanesulfonic acid, phosphoric acid, ethanesulfonic acid, formic acid, p-toluenesulfonic acid, acetic acid, acetoacetic acid, pyruvic acid, pectic acid, butyric acid, caproic acid, benzenesulfonic acid, heptanoic acid, undecanoic acid, benzoic acid, salicylic acid, lauric acid, 2-(4 -Hydroxybenzoyl)benzoic acid, cinnamic acid, camphoric acid, cyclopentanepropionic acid, 3-hydroxy-2-naphthoic acid, camphorsulfonic acid, digluconic acid, niacin, pamoic acid, propionic acid, persulfuric acid ,,,
  • the present invention also provides a pharmaceutical composition of the GLP-1/GCG receptor dual agonist polypeptide compound, the pharmaceutical composition comprising: using any of the above GLP-1/GCG receptor dual agonist polypeptide compounds or a pharmaceutically acceptable salt thereof It is composed of effective raw materials, together with a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a medicament containing the above-mentioned GLP-1/GCG receptor dual agonist polypeptide compound, the medicament is any of the capsules, tablets, sprays, inhalants, injections, patches mentioned in pharmacy , emulsion, film, powder or compound preparation, the medicament is composed of GLP-1/GCG receptor dual agonist polypeptide compound and pharmaceutically acceptable pharmaceutical excipients, carriers or diluents.
  • the present invention also provides the GLP-1/GCG receptor dual agonist polypeptide compound of the present invention, its pharmaceutically acceptable salt, its pharmaceutical composition or its medicament in the preparation of a medicament for the treatment of metabolic diseases or disorders Applications.
  • the metabolic disease or disorder is diabetes, NAFLD, NASH, hyperlipidemia or obesity.
  • the diabetes is type 1 diabetes, T2DM or gestational diabetes.
  • the medicament is for the treatment of more than one metabolic disease or disorder, eg, diabetes and NAFLD, NASH or obesity; obesity and NASH or NAFLD; diabetes, NASH and obesity; diabetes, NAFLD and obesity; or diabetes and obesity .
  • the GLP-1/GCG receptor dual agonist polypeptide compound of the present invention has the functions of promoting weight loss and preventing weight gain while lowering blood sugar more effectively, and reversing insulin resistance. , modulates lipid metabolism with unexpected beneficial effects compared with existing drugs.
  • the agonistic activity of the polypeptide compound of the present invention on GLP-1 receptor and GCG receptor is higher than that of the natural ligands of each receptor, while the agonistic activity on GIP receptor is lower.
  • the polypeptide compound provided by the invention has stable chemical properties, is not easily degraded by DPP-IV and NEP in the body, and is not easily filtered by the glomerulus. Generation dynamics characteristics.
  • the polypeptide compound provided by the present invention has improved biophysical properties, and the solubility at neutral pH and pH 4.5 is higher than that of natural GLP-1 and GCG, and has properties that are beneficial to formulations.
  • the polypeptide compound provided by the invention has low immunogenicity, and the therapeutic effect on metabolic diseases such as T2DM, obesity, NAFLD, NASH and hyperlipidemia is better than that of the existing marketed drugs. Therefore, the polypeptide compound provided by the present invention is suitable as an active ingredient of medicines for the treatment of metabolic diseases, such as diabetes, obesity, hyperlipidemia, NAFLD, NASH and the like.
  • Figure 1 shows the long-acting hypoglycemic effect of a single dose of each test substance in db/db mice in a non-fasted state
  • Figure 2 shows the hypoglycemic effect of each test substance in the oral glucose tolerance test after long-term administration of DIO mice for 21 days;
  • Figure 3 shows the in vitro immunogenicity of each test substance.
  • the 12-position Lys can be Fmoc-Lys(Alloc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Lys(Mtt)-OH or Fmoc-Lys(ivDde)-OH, etc.
  • the Fmoc-Lys(Dde)-OH protection strategy was adopted, and the N-terminal His was Boc-His(Boc)-OH.
  • the crude target polypeptide was dissolved in water, filtered with a 0.25 ⁇ m microporous membrane, and then purified by a Shimadzu preparative reverse-phase HPLC system. Chromatographic conditions were C18 reversed-phase preparative column (250mm ⁇ 20mm, 12 ⁇ m); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: methanol (V/V); flow rate was 8mL/min; detection wavelength is 214nm. A linear gradient (20%B ⁇ 70%B/30min) was used for elution, the target peak was collected, and 0.14g of pure product was obtained by lyophilization after removing methanol. The purity was greater than 98%. The molecular weight of the target polypeptide was confirmed by LC-MS.
  • the synthetic method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.16 g of pure product.
  • the synthesis method was the same as that in Example 1, and the target peak was collected and lyophilized to obtain 0.13 g of pure product.
  • the 12-position Lys can be Fmoc-Lys(Alloc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Lys(Mtt)-OH or Fmoc-Lys(ivDde)-OH, etc.
  • the Fmoc-Lys(Dde)-OH protection strategy was adopted, and the N-terminal His was Boc-His(Boc)-OH.
  • the crude target polypeptide was dissolved in water, filtered through a 0.25 ⁇ m microporous membrane, and then purified by a Shimadzu preparative reverse-phase HPLC system. Chromatographic conditions were C18 reversed-phase preparative column (250mm ⁇ 20mm, 12 ⁇ m); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: methanol (V/V); flow rate was 8mL/min; detection wavelength is 214nm. A linear gradient (20%B ⁇ 80%B/30min) was used for elution, the target peak was collected, and 0.18g of pure product was obtained by lyophilization after removing methanol. The purity was greater than 98%. The molecular weight of the target polypeptide was confirmed by LC-MS.
  • the synthetic method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.17g of pure product.
  • the synthetic method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.15 g of pure product.
  • the synthesis method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.15 g of pure product.
  • the synthetic method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.16 g of pure product.
  • the synthesis method was the same as that in Example 1, and the target peak was collected and lyophilized to obtain 0.14 g of pure product.
  • the synthetic method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.17g of pure product.
  • the synthetic method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.16 g of pure product.
  • the synthetic method was the same as that of Example 4, and the target peak was collected and lyophilized to obtain 0.14g of pure product.
  • the synthetic method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.13 g of pure product.
  • the synthetic method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.15 g of pure product.
  • the synthetic method was the same as that of Example 1, and the target peak was collected and lyophilized to obtain 0.16 g of pure product.
  • the synthesis method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.15 g of pure product.
  • the synthetic method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.16 g of pure product.
  • the synthesis method was the same as that in Example 4, and the target peak was collected and lyophilized to obtain 0.15 g of pure product.
  • the agonistic effect of polypeptide compounds on the receptor is determined by functional assays that measure the cAMP response of HEK-293 cell lines stably expressing the human GLP-1 receptor, GCG receptor or GIP receptor.
  • Cells stably expressing the above three receptors were split into T175 flasks and grown overnight in medium (DMEM/10% FBS) to near confluence, then the medium was removed and cells were washed with PBS without calcium and magnesium, then Protease treatment with Accutase enzyme.
  • Detached cells were washed and resuspended in assay buffer (20 mM HEPES, 0.1% BSA, 2 mM IBMX, 1 x HBSS) and cell density was determined and aliquots of 25 ⁇ L were aliquoted into 96-well plates. in the hole. For measurements, 25 [mu]L of a solution of the test polypeptide compound in assay buffer was added to the wells, followed by incubation at room temperature for 30 minutes. The cAMP content of cells was determined based on homogeneous time-resolved fluorescence (HTRF) using a kit from Cisbio.
  • assay buffer 20 mM HEPES, 0.1% BSA, 2 mM IBMX, 1 x HBSS
  • HTRF reagent diluted in lysis buffer (kit component)
  • the plate was incubated for 1 hour and then the fluorescence ratio at 665/620 nm was measured.
  • the in vitro potency of agonists is quantified by measuring the concentration that elicits 50% activation of the maximal response ( EC50 ).
  • the detection data (nM) in the examples of the present patent application are shown in Table 1 below. Although the detection data is stated with a certain number of significant figures, it should not be considered that the data has been determined to be exactly the number of significant figures.
  • Table 1 EC 50 values of polypeptide compounds for human GLP-1 receptor, GCG receptor and GIP receptor (expressed in nM)
  • SEQ ID NO: 13 0.049 0.059 2869.9
  • SEQ ID NO: 14 0.035 0.062 3215.6
  • SEQ ID NO: 15 0.061 0.052 3015.3
  • SEQ ID NO: 16 0.077 0.060 3225.6
  • SEQ ID NO: 17 0.075 0.056 3568.6
  • SEQ ID NO: 18 0.072 0.061 3348.5
  • the agonistic activity of all polypeptide compounds on GLP-1 receptor is higher than that of natural GLP-1, and the agonistic activity of most polypeptide compounds on GCG receptor is also higher than that of natural GCG. Shows weaker agonistic activity of GIP receptors.
  • SEQ ID NO: 6 94 100 >8 >8 SEQ ID NO: 7 93 100 >8 >8 SEQ ID NO: 8 95 98 >8 >8 SEQ ID NO: 9 90 99 >8 >8 SEQ ID NO: 10 89 99 >8 >8 SEQ ID NO: 11 88 100 >8 >8 SEQ ID NO: 12 93 98 >8 >8 SEQ ID NO: 13 95 97 >8 >8 SEQ ID NO: 14 94 100 >8 >8 SEQ ID NO: 15 92 100 >8 >8 SEQ ID NO: 16 94 99 >8 >8 SEQ ID NO: 17 90 98 >8 >8 SEQ ID NO: 18 88 100 >8 >8 >8
  • the solubility of the polypeptide compound of the present invention is greatly improved under the pH condition of the injection solution acceptable to the body, and has the characteristics that are beneficial to the formulation.
  • the polypeptide compounds of the present invention also have high solubility at pH 4.5, a property that may allow co-formulation for combination therapy with insulin or insulin derivatives.
  • the polypeptide compounds of the present invention also have high stability under pH 4.5 and neutral pH conditions.
  • test sample was incubated with purified human DPP-IV or NEP enzyme at 37°C for 0, 2, 4, and 8 hours.
  • the peak area of the residual sample in the solution at each time point was measured by HPLC, and the half-life of the sample was calculated. The results are shown in the table. 3 shown.
  • SEQ ID NO: 7 >8 >8 SEQ ID NO: 8 >8 >8 SEQ ID NO: 9 >8 >8 SEQ ID NO: 11 >8 >8 SEQ ID NO: 12 >8 >8 SEQ ID NO: 13 >8 >8 SEQ ID NO: 14 >8 >8 SEQ ID NO: 15 >8 >8 SEQ ID NO: 17 >8 >8 SEQ ID NO: 18 >8 >8
  • Rats were administered a subcutaneous (s.c.) injection of 50 nmol/kg and blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 16, 24, 36 and 48 hours post-dose. Plasma samples were analyzed by LC-MS after protein precipitation using acetonitrile. Pharmacokinetic parameters and half-life were calculated using WinonLin 5.2.1 (non-compartmental model) (Table 4).
  • SEQ ID NO: 8 3.9 539 SEQ ID NO: 9 4.6 551 SEQ ID NO: 11 11.5 541 SEQ ID NO: 12 12.6 561
  • the in vivo half-life of the polypeptide compound of the present invention is significantly prolonged, and has the pharmacokinetic characteristics supporting once-daily or once-weekly administration.
  • mice Male db/db mice were randomly divided into groups of 6 mice. The blank group was subcutaneously injected with normal saline (10 mg/kg), and the administration group was divided into 6 groups. During the experiment, the mice were free to eat and drink, and the mice were subcutaneously injected with 25 nmol/kg of liraglutide, semaglutide, SEQ in a non-fasting state. ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 12. Blood glucose levels of mice in each group were measured with a blood glucose meter at 0 h before administration and at 4, 6, 24 and 48 h after administration.
  • the results of the hypoglycemic experiments in db/db mice show that the polypeptide compounds of the present invention show a long-acting hypoglycemic activity superior to that of the positive control drugs liraglutide and semaglutide.
  • mice Male C57BL/6J mice, weighing about 22 g, with a total of 42 models in the model group, were fed with D12492 high-fat diet from Research Diets for 18 weeks to establish the DIO mouse model.
  • the blank control group was fed with standard rat chow (control standard diet group).
  • the DIO mice in each group were randomly divided into 7 groups according to their body weight, with 6 mice in each group, namely the normal saline group (control high-fat diet group), the positive control group (liraglutide and semaglutide) and the control group.
  • Test sample group SEQ ID NO: 8, 9, 11, 12).
  • control standard diet group and the control high-fat diet group were subcutaneously injected twice a day with normal saline (10mg/kg), liraglutide, SEQ ID NO: 8, and SEQ ID NO: 9 groups were subcutaneously injected twice a day (25nmol/kg), semaglutide,
  • SEQ ID NO: 11 and SEQ ID NO: 12 groups were subcutaneously injected (25 nmol/kg) once a day, and the dosing cycle was 21 days.
  • the body weight changes of the mice were recorded every day, and nuclear magnetic resonance (NMR) was used to measure body fat before and at the end of the experiment.
  • NMR nuclear magnetic resonance
  • mice in each group were fasted for 12 h and then orally administered glucose (1.5 g/kg) and The blood glucose values of each group of mice were measured at 15, 30, 60 and 120 min after glucose administration using a blood glucose meter (Table 5).
  • the results of the hypoglycemic experiment show that the polypeptide compound of the present invention exhibits hypoglycemic activity equivalent to that of the positive control drugs liraglutide and semaglutide.
  • mice Male db/db mice were randomly divided into groups of 6 mice. After one week of adaptive feeding, tail blood was taken to measure the initial HbA1c value and fasting blood glucose value before the start of treatment.
  • the blank group was subcutaneously injected with normal saline (10 mg/kg) twice a day, and the administration group was divided into 6 groups. twice daily), SEQ ID NO: 9 (twice daily), SEQ ID NO: 11 (once daily), SEQ ID NO: 12 (once daily).
  • the treatment period was 5 weeks. After the treatment, the mice were fasted overnight to measure the fasting blood glucose value, and at the same time, blood was taken to measure the HbA1c (%) value (Tables 6 and 7).
  • PBMCs peripheral blood mononuclear cells
  • Stimulation index was calculated by dividing the proliferative response (cpm) for each donor's test wells by the proliferative response to the medium treatment (cpm), with an SI greater than 2.0 considered positive.
  • Donor response percentages were calculated by dividing the number of positive donors over the entire time course (5-8 days) as a percentage of the total number of donors tested.
  • the donor response ratio of the polypeptide compound of the present invention is lower than that of liraglutide and semaglutide, indicating that the polypeptide compound of the present invention has low immunogenicity.

Abstract

L'invention concerne un composé polypeptidique double agoniste du récepteur de GLP-1/glucagon (GCG). Le composé polypeptidique double agoniste du récepteur de GLP-1/GCG a pour fonctions de favoriser la perte de poids et de prévenir la prise de poids tout en abaissant la glycémie, en inversant l'insulinorésistance et en régulant le métabolisme lipidique. Le composé polypeptidique a une activité agoniste plus élevée sur un récepteur de GLP-1 et un récepteur de GCG que les ligands naturels pour les récepteurs, et a une activité agoniste plus faible sur un récepteur de GIP. Le composé polypeptidique selon la présente invention présente des propriétés chimiques stables et une faible immunogénicité, et est approprié pour être utilisé en tant que principe actif de médicaments pour le traitement de maladies métaboliques, telles que le diabète, l'obésité, l'hyperlipidémie, la NAFLD et la NASH.
PCT/CN2021/131369 2020-11-27 2021-11-18 Double agoniste du récepteur glp-1/glucagon et son application WO2022111370A1 (fr)

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CN116063455A (zh) * 2022-07-04 2023-05-05 北京惠之衡生物科技有限公司 一种glp-1受体和gcg受体共激动多肽衍生物及其应用

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