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WO2024213022A1 - Analogues d'incrétine et leur procédé de préparation, et utilisation - Google Patents

Analogues d'incrétine et leur procédé de préparation, et utilisation Download PDF

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Publication number
WO2024213022A1
WO2024213022A1 PCT/CN2024/087112 CN2024087112W WO2024213022A1 WO 2024213022 A1 WO2024213022 A1 WO 2024213022A1 CN 2024087112 W CN2024087112 W CN 2024087112W WO 2024213022 A1 WO2024213022 A1 WO 2024213022A1
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WIPO (PCT)
Prior art keywords
incretin analog
cys
incretin
lys
polypeptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/087112
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English (en)
Chinese (zh)
Inventor
冯军
东圆珍
徐宏江
申恒巧
赵梦佳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Duomirui Biotechnology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Shanghai Duomirui Biotechnology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Filing date
Publication date
Application filed by Shanghai Duomirui Biotechnology Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Shanghai Duomirui Biotechnology Co Ltd
Priority to CN202480024633.8A priority Critical patent/CN121002051A/zh
Publication of WO2024213022A1 publication Critical patent/WO2024213022A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • 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 disclosure relates to the field of therapeutic polypeptides, and in particular to incretin analogs and preparation methods and uses thereof.
  • Glucagon-like peptide-1 (GLP-1) is a hormone secreted by the L cells of the small intestine and belongs to the incretin hormone. GLP-1 acts on pancreatic ⁇ cells to promote the synthesis and secretion of insulin. It can also stimulate the proliferation and differentiation of pancreatic ⁇ cells and inhibit the apoptosis of pancreatic ⁇ cells, thus protecting the function of the pancreas. It also has the effects of suppressing appetite and delaying gastric emptying, achieving the effect of lowering blood sugar through these effects.
  • GIP Glucose-dependent insulinotropic polypeptide
  • GLP-1 analogs have dose-dependent side effects such as nausea and vomiting in clinical practice, which reduces patients' compliance with medication.
  • the incretin effect of GIP is weakened in patients with type 2 diabetes (T2DM), which may be related to the downregulation of receptors.
  • T2DM type 2 diabetes
  • Studies have shown that improving blood sugar control through anti-diabetic treatment can restore the pancreatic function of GIP in patients with T2DM, indicating that co-stimulation of GLP-1R and GIPR can play a synergistic hypoglycemic effect.
  • GLP-1R GIPR/glucagon-like peptide-1 receptor
  • the present disclosure provides an incretin analog, and also provides a pharmaceutical composition comprising the incretin analog, a preparation method of the incretin analog and an application thereof.
  • the incretin analog disclosed in the present disclosure is a single molecule dual receptor agonist, which can simultaneously stimulate GLP-1R and GIPR.
  • the present disclosure provides a polypeptide or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the polypeptide optionally has a C-terminal amidation modification.
  • the present disclosure provides an incretin analog or a pharmaceutically acceptable salt thereof, comprising a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • the C-terminus of the polypeptide has a -COOH group, i.e., the polypeptide has a C-terminus with a free carboxyl group. In some embodiments, the C-terminus of the polypeptide has a -CONH 2 group, i.e., the polypeptide has a C-terminus amidation modification, i.e., the polypeptide has an amidation-modified C-terminus.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for preparing the incretin analog or a pharmaceutically acceptable salt thereof, comprising preparing the polypeptide of the present disclosure by chemical synthesis and/or recombinant expression, preparing the modifier of the present disclosure by chemical synthesis, and linking the modifier to the polypeptide via Cys in the polypeptide.
  • the present disclosure provides use of the incretin analog or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament.
  • the present disclosure provides a method for treating a disease in a subject in need thereof, comprising administering to the subject an incretin analog or a pharmaceutically acceptable salt thereof of the present disclosure, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an incretin analog or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • Figures 1 and 2 are the weight change rate curves of mice after drug administration
  • FIG3 is a blood glucose level curve of mice in a type 2 diabetes mouse model after administration
  • Figure 4 shows the body weight change rate curve of DIO mice after drug administration.
  • the present disclosure provides a polypeptide or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the polypeptide optionally has a C-terminal amidation modification.
  • the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 16), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the polypeptide optionally has a C-terminal amidation modification.
  • said X2 is Aib.
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X2 is Aib
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X20 is Cys.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • X2 is Aib, X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 16), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • X2 is Aib.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Tyr
  • X13 is selected from Cys or Tyr
  • X16 is selected from Cys or Lys
  • X20 is selected from Cys or Lys
  • X21 is selected from Cys or Leu
  • X24 is selected from Cys or Gln
  • X27 is selected from Cys or Leu, and there is only one Cys in the amino acid sequence.
  • X20 is Cys.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gin
  • X27 is selected from Leu, Ile or Val.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gin
  • X27 is selected from Leu, Ile or Val.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is GIn
  • X27 is Leu.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is GIn
  • X27 is Leu.
  • the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Tyr
  • X13 is selected from Tyr or Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is GIn
  • X27 is Leu.
  • polypeptide or a pharmaceutically acceptable salt thereof comprises any one of the following amino acid sequences:
  • amino acid sequence of the polypeptide is selected from any one of the following:
  • the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in SEQ ID NO:1, 3, 5 or 7. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in SEQ ID NO:3. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence as shown in SEQ ID NO:7.
  • the amino acid sequence of the polypeptide is as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In some embodiments, the amino acid sequence of the polypeptide is shown in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, the amino acid sequence of the polypeptide is shown in SEQ ID NO: 1, 3, 5 or 7. In some embodiments, the amino acid sequence of the polypeptide is shown in SEQ ID NO: 3. In some embodiments, the amino acid sequence of the polypeptide is shown in SEQ ID NO: 7.
  • the polypeptide in the above polypeptide or its pharmaceutically acceptable salt, has a C-terminus with a free carboxyl group. In other embodiments, in the above polypeptide or its pharmaceutically acceptable salt, the polypeptide has a C-terminus amidation modification.
  • polypeptide or its pharmaceutically acceptable salt of the present invention is linked to the substituent of the present invention via Cys in the polypeptide to obtain the incretin analog of the present invention.
  • polypeptide or its pharmaceutically acceptable salt is linked to the substituent of the present invention via the thiol group of Cys in the polypeptide.
  • the present disclosure provides an incretin analog or a pharmaceutically acceptable salt thereof, which comprises the above polypeptide and a substituent disclosed herein.
  • the pancreatic analogs or pharmaceutically acceptable salts thereof of the present disclosure comprise the above-mentioned polypeptide, and a substituent, wherein the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the present disclosure provides an incretin analog or a pharmaceutically acceptable salt thereof, comprising a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein,
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • the present disclosure provides an incretin analog or a pharmaceutically acceptable salt thereof, comprising a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 16), wherein,
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • said X2 is Aib.
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X2 is Aib
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X20 is Cys.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • X2 is Aib, X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 16), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • said X2 is Aib.
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X2 is Aib
  • X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • X20 is Cys.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val.
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X2 is Aib
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu.
  • X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • X2 is Aib, X12 is Tyr, X13 is selected from Tyr or Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 17), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS (SEQ ID NO: 16), wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide; the polypeptide optionally has a C-terminal amidation modification.
  • X2 is Aib.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr or Ile,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X27 is selected from Cys, Leu, Ile or Val, and
  • the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Tyr
  • X13 is selected from Cys or Tyr
  • X16 is selected from Cys or Lys
  • X20 is selected from Cys or Lys
  • X21 is selected from Cys or Leu
  • X24 is selected from Cys or Gln
  • X27 is selected from Cys or Leu, and there is one and only one Cys in the amino acid sequence; and the substituent is linked to the polypeptide through the Cys in the polypeptide.
  • X20 is Cys.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val; and the substituent is linked to the polypeptide through the thiol group of Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Tyr, Lys, Ile or Ser
  • X13 is Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is selected from Leu, Ile or Val; and the substituent is linked to the polypeptide through the thiol group of Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is selected from Lys, Ile or Ser
  • X13 is selected from Tyr, Ile, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu; and the substituent is linked to the polypeptide through the thiol group of Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Lys
  • X13 is selected from Tyr, Ala or Aib
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu; and the substituent is linked to the polypeptide through the thiol group of Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is Aib
  • X12 is Tyr
  • X13 is selected from Tyr or Ile
  • X16 is Lys
  • X20 is Cys
  • X21 is Leu
  • X24 is Gln
  • X27 is Leu; and the substituent is linked to the polypeptide through the Cys in the polypeptide.
  • the incretin analog or a pharmaceutically acceptable salt thereof comprises a polypeptide and a substituent, wherein the polypeptide comprises any one selected from the following amino acid sequences:
  • the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analog consists of a polypeptide and a substituent, wherein the polypeptide comprises any one selected from the following amino acid sequences:
  • the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is selected from any one of the following:
  • the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analog or a pharmaceutically acceptable salt thereof comprises a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analog or a pharmaceutically acceptable salt thereof comprises a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 3, 5 or 7. In some such embodiments, the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:3. In some such embodiments, the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:7.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and the substituent is linked to the polypeptide through Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and the substituent is linked to the polypeptide through Cys in the polypeptide.
  • the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:1, 3, 5 or 7.
  • the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:3.
  • the polypeptide comprises an amino acid sequence as shown in SEQ ID NO:7.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and the substituent is linked to the polypeptide through Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and the substituent is linked to the polypeptide through Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in SEQ ID NO: 1, 3, 5 or 7; and the substituent is linked to the polypeptide through Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in SEQ ID NO:3; and the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the incretin analogue consists of a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is as shown in SEQ ID NO:7; and the substituent is linked to the polypeptide via Cys in the polypeptide.
  • the substituent is linked to the polypeptide via Cys at position 13, 16, 20, 21, 24, or 27 of the polypeptide. In some embodiments, the substituent is linked to the polypeptide via Cys at position 20 of the polypeptide. In some embodiments, the substituent is linked to the polypeptide via Cys at position 20 of the polypeptide whose amino acid sequence is shown in SEQ ID NO:7.
  • the substituent is linked to the polypeptide via the thiol group of Cys at position 13, 16, 20, 21, 24 or 27 of the polypeptide. In some embodiments, the substituent is linked to the polypeptide via the thiol group of Cys at position 20 of the polypeptide. In some embodiments, the substituent is linked to the polypeptide via the thiol group of Cys at position 20 of the polypeptide having an amino acid sequence as shown in SEQ ID NO:7.
  • the substituent is connected to the polypeptide by forming a thioether bond with the thiol group of Cys at position 13, 16, 20, 21, 24 or 27 of the polypeptide. In some embodiments, the substituent is connected to the polypeptide by forming a thioether bond with the thiol group of Cys at position 20 of the polypeptide. In some embodiments, the substituent is connected to the polypeptide by forming a thioether bond with the thiol group of Cys at position 20 of the polypeptide whose amino acid sequence is shown in SEQ ID NO:7.
  • the substituent comprises a fatty acid group.
  • the fatty acid group comprises a carbon chain comprising at least 8 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 10 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 12 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 14 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 16 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 18 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 20 consecutive -CH 2 -structural units.
  • the fatty acid group comprises a carbon chain comprising 8-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 10-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 12-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 14-20 consecutive -CH 2 - structural units.
  • the fatty acid group comprises a carbon chain comprising 8, 10, 12, 14, 16, 18, or 20 consecutive -CH2- structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 16 or 18 consecutive -CH2- structural units.
  • the structure of the fatty acid group is as follows:
  • n is an integer between 8 and 20.
  • the fatty acid groups may be bound to albumin.
  • the substituent further comprises a linker.
  • the linker is connected to the fatty acid group via an amide bond.
  • the structure of the fatty acid group is as shown in Formula I, wherein n is an integer between 8 and 20, and the wavy line In some embodiments, n is an integer between 10 and 20. In some embodiments, n is an integer between 12 and 20. In some embodiments, n is an integer between 14 and 20. In some embodiments, n is 8, 10, 12, 14, 16 or 18. In some embodiments, n is 16 or 18.
  • the substituent has the following structure:
  • Lk represents a linker
  • R1 is a fatty acid group of the structure shown in Formula I
  • n is an integer from 8 to 20
  • the wavy line in Formula I represents the connection position between R1 and Lk
  • the wavy line in Formula II represents the connection position between the substituent and the polypeptide of the present disclosure.
  • n is an integer between 10 and 20. In some embodiments, n is an integer between 12 and 20. In some embodiments, n is an integer between 14 and 20. In some embodiments, n is 8, 10, 12, 14, 16, or 18. In some embodiments, n is 16 or 18.
  • the Lk is selected from one or more combinations of Ala, D-Ala, Arg, Asp, Asn, Glu, D-Glu, ⁇ -Glu, Gln, Gly, Lys, ⁇ -Lys, Pro, Phe, Ser or AEEA, or is missing; preferably one or more combinations of Asp, Glu, ⁇ -Glu, Gly, Ser, AEEA, Lys or ⁇ -Lys; more preferably one or more combinations of Glu, ⁇ -Glu, AEEA, Lys or ⁇ -Lys. In some embodiments, the Lk is selected from one or more combinations of ⁇ -Glu, AEEA or ⁇ -Lys.
  • the -Lk- is -AEEA- ⁇ -Glu- ⁇ -Glu-, and the substituent structure is: In some embodiments, the -Lk- is - ⁇ -Glu-AEEA-AEEA-, and the substituent structure is: In some embodiments, the -Lk- is - ⁇ -Glu- ⁇ -Lys- ⁇ -Lys-, and the structure of the substituent is:
  • the structure of the substituent is as shown in Formula II, wherein the Lk represents a linker and is selected from one or a combination of ⁇ -Glu, AEEA or ⁇ -Lys, R1 is a fatty acid group of the structure shown in Formula I, n is an integer from 14 to 20, the wavy line in Formula I represents the connection position between R1 and Lk, and the wavy line in Formula II represents the connection position between the substituent and the polypeptide of the present disclosure; preferably, n is 8, 10, 12, 14, 16 or 18; more preferably, n is 16 or 18.
  • the substituent is selected from the following structures: Wherein, the wavy lines in Formulae II-1, II-2, II-3, II-4, II-5 and II-6 indicate the connection position of the substituent to the polypeptide of the present disclosure.
  • the incretin analog or a pharmaceutically acceptable salt thereof comprises a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is YAibEGTFTSDYSYYLEKQAACLFVQWLLAGGPSSGAPPPS, and the polypeptide optionally has a C-terminal amidation modification; the substituent is connected to the polypeptide via the thiol group of Cys in the polypeptide, and the structure of the substituent is as shown in Formula II-1, II-2, II-3, II-4, II-5 or II-6. In some embodiments, the structure of the substituent is as shown in Formula II-1. In some embodiments, the structure of the substituent is as shown in Formula II-2.
  • the structure of the substituent is as shown in Formula II-3. In some embodiments, the structure of the substituent is as shown in Formula II-4. In some embodiments, the structure of the substituent is as shown in Formula II-5. In some embodiments, the structure of the substituent is as shown in Formula II-6.
  • the incretin analog or a pharmaceutically acceptable salt thereof comprises a polypeptide and a substituent, wherein the amino acid sequence of the polypeptide is YAibEGTFTSDYSYILEKQAACLFVQWLLAGGPSSGAPPPS, and the polypeptide optionally has a C-terminal amidation modification; the substituent is connected to the polypeptide via the thiol group of Cys in the polypeptide, and the structure of the substituent is as shown in Formula II-1, II-2, II-3, II-4, II-5 or II-6. In some embodiments, the structure of the substituent is as shown in Formula II-1. In some embodiments, the structure of the substituent is as shown in Formula II-2.
  • the structure of the substituent is as shown in Formula II-3. In some embodiments, the structure of the substituent is as shown in Formula II-4. In some embodiments, the structure of the substituent is as shown in Formula II-5. In some embodiments, the structure of the substituent is as shown in Formula II-6.
  • the substituents attached to the polypeptides of the present disclosure can non-covalently bind to albumin via the fatty acid group, thereby extending the half-life of the incretin analog in vivo.
  • the polypeptide in some embodiments, in the above-mentioned incretin analogs or pharmaceutically acceptable salts thereof, the polypeptide has a C-terminus with a free carboxyl group. In other embodiments, in the above-mentioned incretin analogs or pharmaceutically acceptable salts thereof, the polypeptide has a C-terminus amidation modification.
  • the incretin analogs provided by the present disclosure have agonist activity of GIPR and GLP-1R, are dual receptor agonists, and are significantly effective in treating diabetes, lowering blood sugar, and reducing body weight.
  • the present disclosure provides a modifier comprising a fatty acid group.
  • the modifier is used to modify the polypeptide of the present disclosure to obtain an incretin analog.
  • the polypeptide connected with the modifier can non-covalently bind to albumin through the fatty acid group, thereby extending the half-life of the incretin analog in vivo.
  • the fatty acid group comprises a carbon chain comprising at least 8 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 10 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 12 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 14 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 16 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 18 consecutive -CH 2 -structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising at least 20 consecutive -CH 2 -structural units.
  • the fatty acid group comprises a carbon chain comprising 8-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 10-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 12-20 consecutive -CH 2 - structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 14-20 consecutive -CH 2 - structural units.
  • the fatty acid group comprises a carbon chain comprising 8, 10, 12, 14, 16, 18, or 20 consecutive -CH2- structural units. In some embodiments, the fatty acid group comprises a carbon chain comprising 16 or 18 consecutive -CH2- structural units.
  • the structure of the fatty acid group is as shown in Formula I, wherein n is an integer between 8-20.
  • the modifier further comprises a linker.
  • the linker is connected to the fatty acid group via an amide bond.
  • the structure of the fatty acid group is as shown in Formula I, wherein n is an integer between 8 and 20, and the wavy line In some embodiments, n is an integer between 10 and 20. In some embodiments, n is an integer between 12 and 20. In some embodiments, n is an integer between 14 and 20. In some embodiments, n is 8, 10, 12, 14, 16 or 18. In some embodiments, n is 16 or 18.
  • the structure of the modifier is as follows:
  • Lk represents a linker
  • R1 is a fatty acid group of the structure shown in Formula I
  • R2 is an iodoacetyl group or a bromoacetyl group
  • n is an integer from 8 to 20
  • the wavy line in Formula I represents the connection position between R1 and Lk.
  • R2 is a bromoacetyl group.
  • n is an integer between 10 and 20. In some embodiments, n is an integer between 12 and 20. In some embodiments, n is an integer between 14 and 20. In some embodiments, n is 8, 10, 12, 14, 16, or 18. In some embodiments, n is 16 or 18.
  • the Lk is selected from one or more combinations of Ala, D-Ala, Arg, Asp, Asn, Glu, D-Glu, ⁇ -Glu, Gln, Gly, Lys, ⁇ -Lys, Pro, Phe, Ser or AEEA, or is missing; preferably one or more combinations of Asp, Glu, ⁇ -Glu, Gly, Ser, AEEA, Lys or ⁇ -Lys; more preferably one or more combinations of Glu, ⁇ -Glu, AEEA, Lys or ⁇ -Lys. In some embodiments, the Lk is selected from one or more combinations of ⁇ -Glu, AEEA or ⁇ -Lys.
  • the -Lk- is -AEEA- ⁇ -Glu- ⁇ -Glu-, and the modifier structure is: In some embodiments, the -Lk- is - ⁇ -Glu-AEEA-AEEA-, and the modifier structure is: In some embodiments, the -Lk- is - ⁇ -Glu- ⁇ -Lys- ⁇ -Lys-, and the structure of the modifier is:
  • the structure of the modifier is as shown in Formula III, wherein the Lk represents a linker and is selected from one or a combination of ⁇ -Glu, AEEA or ⁇ -Lys, R1 is a fatty acid group of the structure shown in Formula I, n is an integer between 14 and 20, and the wavy line in Formula I represents the connection position between R1 and Lk; preferably, n is 8, 10, 12, 14, 16 or 18; more preferably, n is 16 or 18.
  • the modifier is selected from the following structures:
  • the present disclosure provides a pharmaceutical composition comprising the incretin analogs of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises the incretin analogs of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition can be a solid preparation, such as a lyophilized preparation.
  • the pharmaceutical composition can be a liquid preparation, such as an aqueous preparation.
  • the present disclosure provides a method for preparing an incretin analog or a pharmaceutically acceptable salt thereof, comprising preparing a polypeptide of the present disclosure by chemical synthesis and/or recombinant expression, preparing a modifier of the present disclosure by chemical synthesis, and linking the modifier to the polypeptide via Cys in the polypeptide.
  • the modifier is linked to the polypeptide via the thiol group of Cys in the polypeptide.
  • polypeptides of the present disclosure can be prepared by chemical synthesis, for example, using solid phase synthesis to prepare the polypeptides of the present disclosure.
  • the polypeptides of the present disclosure can be prepared by recombinant expression methods, for example, by culturing a host cell containing a DNA sequence encoding the polypeptide in a suitable culture medium under conditions that allow polypeptide expression.
  • the polypeptides of the present disclosure can be prepared by a combination of recombinant expression and chemical synthesis.
  • host cells suitable for expressing these polypeptides include Escherichia coli or CHO cells.
  • the method for preparing the polypeptide of the present disclosure comprises the following steps:
  • a step of purifying the crude polypeptide may be further included.
  • the purification method includes but is not limited to reverse phase chromatography or ion exchange chromatography, preferably reverse phase chromatography.
  • the resin is Wang resin or MBHA resin.
  • the side chain protecting group scavenger is selected from one, two or more combinations of thioanisole, triisopropylsilane, phenol, water, 1,2-ethanedithiol or meta-cresol.
  • the strong acid is trifluoroacetic acid (TFA).
  • step (1) comprises:
  • step (c) Repeat step (b) to sequentially couple the remaining amino acids. After the last amino acid is coupled, the amino protecting group is removed with a removing agent, and the resin is washed with a solvent to obtain a resin peptide.
  • the sequential coupling of the remaining amino acids is to connect the amino acids one by one from the C-terminus to the N-terminus according to the amino acid sequence of the polypeptide.
  • the amino protecting group is selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenyl-methoxycarbonyl (Fmoc), preferably 9-fluorenyl-methoxycarbonyl (Fmoc).
  • the solvent in step (1) is selected from N,N-dimethylformamide (DMF), dichloromethane (DCM) or N-methylpyrrolidone (NMP), preferably DMF or DCM.
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • NMP N-methylpyrrolidone
  • the removing agent in step (1) is selected from a DMF solution of piperidine (v/v) at a concentration of 10%-40%, preferably a DMF solution of piperidine (v/v) at a concentration of 20-25%.
  • the time required for removing the amino protecting group can be selected from 20-50 min, preferably 25-35 min.
  • the condensation reagent is selected from one or a combination of carbodiimide-type reagents, benzotriazolium salt-type reagents or 1-hydroxybenzotriazole (HOBt).
  • the carbodiimide-type reagent is selected from one of dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).
  • the benzotriazolium salt-type reagent is selected from one of 2-(1H-benzotriazolyl L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), hexafluorophosphate benzotriazole-1-oxy tris (dimethylamino) phosphorus (BOP) or hexafluorophosphate benzotriazole-1-yl-oxy tripyrrolidinophosphorus (PyBOP).
  • the condensation reagents are DIC and HOBt, or TBTU and HOBt; preferably DIC and HOBt.
  • the present disclosure provides the use of the incretin analogs of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in the preparation of a medicament.
  • the medicament is used to treat diseases including but not limited to hyperglycemia, diabetes, impaired glucose tolerance or obesity.
  • the present disclosure provides a method for treating a disease in a subject in need thereof, comprising administering to the subject an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease includes, but is not limited to, hyperglycemia, diabetes, impaired glucose tolerance, or obesity.
  • non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young (MODY), or gestational diabetes.
  • the present disclosure provides the use of the incretin analog or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diabetes. In one embodiment, the present disclosure provides the use of the incretin analog or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type 2 diabetes. In one embodiment, the present disclosure provides the use of the incretin analog or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating obesity.
  • the present disclosure provides the use of the pharmaceutical composition in the preparation of a medicament for treating diabetes. In one embodiment, the present disclosure provides the use of the pharmaceutical composition in the preparation of a medicament for treating type 2 diabetes. In one embodiment, the present disclosure provides the use of the pharmaceutical composition in the preparation of a medicament for treating obesity.
  • the present disclosure provides a method for treating diabetes in a subject in need, comprising administering to the subject an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating type 2 diabetes in a subject in need, comprising administering to the subject an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating obesity in a subject in need, comprising administering to the subject an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating diabetes in a subject in need, comprising administering to the subject a therapeutically effective amount of an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating type 2 diabetes in a subject in need, comprising administering to the subject a therapeutically effective amount of an incretin analog of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an incretin analog or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • Embodiment 1 A polypeptide or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence as shown in YX 2 EGTFTSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FVX 24 WLX 27 AGGPSSGAPPPS, wherein:
  • X2 is selected from Aib or Ala
  • X12 is selected from Tyr, Lys, Ile or Ser,
  • X13 is selected from Cys, Tyr, Ile, Ala or Aib,
  • X 16 is selected from Cys or Lys
  • X 20 is selected from Cys or Lys
  • X 21 is selected from Cys or Leu
  • X 24 is selected from Cys or Gln,
  • X 27 is selected from Cys, Leu, Ile or Val, and there is one and only one Cys in the amino acid sequence; and the polypeptide optionally has a C-terminal amidation modification.
  • Embodiment 2 The polypeptide or pharmaceutically acceptable salt thereof according to Embodiment 1, wherein X2 is Aib.
  • Embodiment 3 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X 13 is selected from Cys, Tyr or Ile.
  • Embodiment 4 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X12 is Tyr, X13 is selected from Cys or Tyr, X16 is selected from Cys or Lys, X20 is selected from Cys or Lys, X21 is selected from Cys or Leu, X24 is selected from Cys or Gln, and X27 is selected from Cys or Leu.
  • Embodiment 5 The polypeptide or pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 4, wherein X 20 is Cys.
  • Embodiment 6 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X12 is selected from Tyr, Lys, Ile or Ser, X13 is Ile, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is selected from Leu, Ile or Val.
  • Embodiment 7 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X 12 is selected from Lys, Ile or Ser, X 13 is selected from Tyr, Ile, Ala or Aib, X 16 is Lys, X 20 is Cys, X 21 is Leu, X 24 is Gln, and X 27 is Leu.
  • Embodiment 8 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X12 is Lys, X13 is selected from Tyr, Ala or Aib, X16 is Lys, X20 is Cys, X21 is Leu, X24 is Gln, and X27 is Leu.
  • Embodiment 9 The polypeptide or pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein X 12 is Tyr, X 13 is selected from Tyr or Ile, X 16 is Lys, X 20 is Cys, X 21 is Leu, X 24 is Gln, and X 27 is Leu.
  • Embodiment 10 A polypeptide or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein the polypeptide or a pharmaceutically acceptable salt thereof comprises an amino acid sequence shown in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
  • Embodiment 11 The polypeptide or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-10, wherein the polypeptide has a C-terminal amidation modification.
  • Embodiment 12 An incretin analog or a pharmaceutically acceptable salt thereof, comprising the polypeptide according to any one of embodiments 1-11, and a substituent, wherein the substituent is linked to the polypeptide via Cys in the polypeptide.
  • Embodiment 13 An incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 12, wherein the substituent is linked to the polypeptide via Cys at position 13, 16, 20, 21, 24 or 27 of the polypeptide; preferably, it is linked to the polypeptide via Cys at position 20 of the polypeptide.
  • Embodiment 14 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 12 or 13, wherein the substituent comprises a fatty acid group.
  • Embodiment 15 An incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 14, wherein the fatty acid group comprises a carbon chain comprising at least 8 consecutive -CH 2 -structural units; preferably, the carbon chain comprises 8-20 consecutive -CH 2 -structural units; more preferably, the carbon chain comprises 8, 10, 12, 14, 16, 18 or 20 consecutive -CH 2 -structural units; most preferably, the carbon chain comprises 16 or 18 consecutive -CH 2 -structural units.
  • Embodiment 16 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 14, wherein the structure of the fatty acid group is as follows:
  • n is an integer between 8 and 20; preferably, n is 8, 10, 12, 14, 16 or 18; more preferably, n is 16 or 18.
  • Embodiment 17 The incretin analog or a pharmaceutically acceptable salt thereof according to any one of Embodiments 12-16, wherein the substituent further comprises a linker.
  • Embodiment 18 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 12 or 13, wherein the structure of the substituent is as follows:
  • Lk represents a linker
  • R1 is The fatty acid group of the structure shown
  • n is an integer between 8 and 20
  • the wavy line in formula I represents the connection position between R1 and Lk
  • the wavy line in formula II represents the connection position between the substituent and the polypeptide.
  • Embodiment 19 An incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 18, wherein Lk is selected from one or a combination of Ala, D-Ala, Arg, Asp, Asn, Glu, D-Glu, ⁇ -Glu, Gln, Gly, Lys, ⁇ -Lys, Pro, Phe, Ser or AEEA, or is absent; preferably one or a combination of Asp, Glu, ⁇ -Glu, Gly, Ser, AEEA, Lys or ⁇ -Lys; more preferably one or a combination of Glu, ⁇ -Glu, AEEA, Lys or ⁇ -Lys.
  • Embodiment 20 The incretin analog or pharmaceutically acceptable salt thereof according to Embodiment 18 or 19, wherein the Lk is selected from one or a combination of ⁇ -Glu, AEEA or ⁇ -Lys.
  • Embodiment 21 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 18, wherein:
  • the Lk is -AEEA- ⁇ -Glu- ⁇ -Glu-, and the substituent structure is:
  • Embodiment 22 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 12 or 13, wherein the substituent is selected from the following structures:
  • the wavy lines in formulae II-1, II-2, II-3, II-4, II-5 and II-6 indicate the connection position between the substituent and the polypeptide.
  • Embodiment 23 The incretin analog or a pharmaceutically acceptable salt thereof according to Embodiment 12, wherein the incretin analog is selected from:
  • Incretin analog 1 its structure is:
  • Incretin analog 6 its structure is:
  • Incretin analog 10 the structure of which is:
  • Incretin analog 14 the structure of which is:
  • Incretin analog 19 its structure is:
  • Incretin analog 20 the structure of which is:
  • Incretin analog 30 the structure of which is:
  • Incretin analog 32 its structure is:
  • Incretin analog 33 its structure is:
  • Incretin analog 34 the structure of which is:
  • Incretin analog 35 its structure is:
  • Incretin analog 36 its structure is:
  • Incretin analog 37 its structure is:
  • Incretin analog 38 its structure is:
  • Incretin analog 39 its structure is:
  • Incretin analog 40 the structure of which is:
  • Incretin analog 41 its structure is:
  • Incretin analog 42 the structure of which is:
  • Incretin analog 43 its structure is:
  • Incretin analog 44 its structure is:
  • Incretin analog 45 its structure is:
  • Incretin analog 46 its structure is:
  • Incretin analog 47 its structure is:
  • Incretin analog 48 its structure is:
  • Incretin analog 49 its structure is:
  • Incretin analog 50 the structure of which is:
  • Incretin analog 51 its structure is:
  • Incretin analog 52 the structure of which is:
  • Incretin analog 53 its structure is:
  • Incretin analog 54 the structure of which is:
  • Incretin analog 55 its structure is:
  • Incretin analog 56 its structure is:
  • Incretin analog 57 its structure is:
  • Incretin analog 58 its structure is:
  • Incretin analog 59 its structure is:
  • Incretin analog 60 its structure is:
  • Incretin analog 61 its structure is:
  • Incretin analog 62 its structure is:
  • Incretin analog 63 its structure is:
  • Incretin analog 64 its structure is:
  • Incretin analog 65 its structure is:
  • Incretin analog 66 its structure is:
  • Incretin analog 67 its structure is:
  • Incretin analog 68 its structure is:
  • Incretin analog 69 its structure is:
  • Incretin analog 70 the structure of which is:
  • Incretin analog 71 its structure is:
  • Incretin analog 72 its structure is:
  • Incretin analog 73 its structure is:
  • Incretin analog 74 its structure is:
  • Incretin analog 75 its structure is:
  • Incretin analog 76 its structure is:
  • Incretin analog 77 its structure is:
  • Incretin analog 78 its structure is:
  • Incretin analog 79 its structure is:
  • Incretin analog 80 its structure is:
  • Incretin analog 81 its structure is:
  • Incretin analog 82 its structure is:
  • Incretin analog 83 its structure is:
  • Or incretin analog 84 whose structure is:
  • Embodiment 24 A pharmaceutical composition comprising the incretin analog or a pharmaceutically acceptable salt thereof according to any one of Embodiments 12-23, and one or more pharmaceutically acceptable excipients.
  • Embodiment 25 Use of the incretin analogue or a pharmaceutically acceptable salt thereof according to any one of Embodiments 12-23, or the pharmaceutical composition according to Embodiment 24 in the preparation of a drug.
  • Embodiment 26 The use according to embodiment 25, wherein the disease for which the medicament is used to treat is hyperglycemia, diabetes, impaired glucose tolerance and/or obesity.
  • Embodiment 27 The use according to embodiment 26, wherein the diabetes is type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the juvenile and/or gestational diabetes.
  • Embodiment 28 A method of treating a disease in a subject in need thereof, comprising administering to the subject the incretin analog or a pharmaceutically acceptable salt thereof according to any one of Embodiments 12-23, or the pharmaceutical composition according to Embodiment 24.
  • Embodiment 29 The method according to embodiment 28, wherein the disease is hyperglycemia, diabetes, impaired glucose tolerance and/or obesity.
  • Embodiment 30 The method according to embodiment 29, wherein the diabetes is type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the juvenile and/or gestational diabetes.
  • Embodiment 31 A modifier having the following structure:
  • Lk represents a linker
  • R1 is The fatty acid group of the structure shown
  • R 2 is iodoacetyl or bromoacetyl
  • n is an integer from 8 to 20
  • the wavy line in Formula I indicates the connection position between R 1 and Lk;
  • Lk is selected from one or more combinations of Ala, D-Ala, Arg, Asp, Asn, Glu, D-Glu, ⁇ -Glu, Gln, Gly, Lys, ⁇ -Lys, Pro, Phe, Ser or AEEA, or is absent; preferably, it is one or more combinations of Asp, Glu, ⁇ -Glu, Gly, Ser, AEEA, Lys or ⁇ -Lys; more preferably, it is one or more combinations of Glu, ⁇ -Glu, AEEA, Lys or ⁇ -Lys.
  • Embodiment 32 The modifier according to embodiment 31, wherein the Lk is selected from one or a combination of ⁇ -Glu, AEEA or ⁇ -Lys.
  • Embodiment 33 The modifier according to embodiment 31, wherein
  • the Lk is -AEEA- ⁇ -Glu- ⁇ -Glu-, and the modifier structure is:
  • Lk is - ⁇ -Glu-AEEA-AEEA-, and the modifier structure is: or,
  • Embodiment 34 The modifier according to embodiment 31, wherein the modifier is selected from the following structures:
  • Embodiment 35 A method for preparing the incretin analog or a pharmaceutically acceptable salt thereof according to any one of embodiments 12-23, comprising preparing the polypeptide according to any one of embodiments 1-11 by chemical synthesis and/or recombinant expression, preparing the modifier according to any one of embodiments 31-34 by chemical synthesis, and linking the modifier to the polypeptide via Cys in the polypeptide.
  • mercapto refers to a -SH group.
  • the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter.
  • the compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present disclosure (including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures) are constituents of the present disclosure.
  • the compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • treatment generally refers to an operation to obtain a desired pharmacological and/or physiological effect.
  • the effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and/or may be therapeutic, in terms of partially or completely stabilizing or curing a disease and/or side effects produced by the disease.
  • treatment encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, inhibiting a disease or disease state, alleviating symptoms of a disease, reducing any direct or indirect pathological consequences of a disease, preventing the metastasis of a disease, slowing the progression of a disease, improving or alleviating the state of a disease, extending the frequency and duration of symptom-free periods, and resolving or improving the prognosis of a disease.
  • a “therapeutically effective amount” is any amount of a drug that protects a subject from the onset of disease or promotes disease regression, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction.
  • the ability of a drug to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • excipient refers to any ingredient other than the active ingredient (e.g., the incretin analogs of the present disclosure).
  • the choice of excipient will depend to a large extent on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • pharmaceutically acceptable excipients include, but are not limited to, excipients, diluents, fillers, binders, disintegrants, solubilizers, stabilizers, colorants, flavorings, surfactants, emulsifiers, buffers or encapsulating materials. The amount of each excipient may vary within the conventional range in the art.
  • “pharmaceutically acceptable salts” may be, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.
  • metal salts include, but are not limited to, salts of alkali metals, such as sodium salts, potassium salts, and the like; salts of alkaline earth metals, such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts, and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
  • amino protecting group refers to a chemical group introduced to protect the amino group participating in the condensation reaction, which can be selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenyl-methoxycarbonyl (Fmoc), preferably 9-fluorenyl-methoxycarbonyl (Fmoc).
  • the terms “subject,” “patient,” or “subject” are used interchangeably.
  • “Subject,” “patient,” or “subject” includes any human or non-human animal.
  • the term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the terms “subject,” “patient,” or “subject” are mammals.
  • the subject, patient, or subject is a mouse.
  • the subject, patient, or subject is a human.
  • the 20th Cys in the polypeptide with an amino acid sequence such as SEQ ID NO:7 refers to the 20th Cys in the sequence, starting with the first amino acid at the N-terminus of SEQ ID NO:7 as position 1.
  • “about” means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, “about” may mean a range of up to ⁇ 5%, such as fluctuations within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of a given specific numerical range. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about” should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values of drug doses, times, step parameters, or conditions are modified by "about” by default.
  • the abbreviations of natural amino acid residues in polypeptides are as follows: Phe or F for phenylalanine, Leu or L for leucine, Ile or I for isoleucine, Met or M for methionine, Val or V for valine, Ser or S for serine, Pro or P for proline, Thr or T for threonine, Ala or A for alanine, Tyr or Y for tyrosine, His or H for histidine, Gln or Q for glutamine, Asn or N for asparagine, Lys or K for lysine, Asp or D for aspartic acid, Glu or E for glutamic acid, Cysteine is Cys or C, Trp or W for tryptophan, Arg or R for arginine, and Gly or G for glycine.
  • the abbreviations of non-natural amino acid residues in polypeptides are as follows: D-alanine is D-Ala, D-glutamic acid is D
  • Aib in the polypeptide is as follows:
  • AEEA means 2-[2-(2-aminoethoxy)ethoxy]acetic acid.
  • ⁇ -Glu (also written as gGlu or ⁇ Glu), which has the following structure:
  • ⁇ -Lys (also written as eLys or ⁇ Lys), which has the following structure:
  • the detection, purification and characterization methods used in the examples are as follows: Tirzepatide used in the examples is from Eli Lilly and Company, and Semaglutide is from Novo Nordisk.
  • the chromatographic column was Kromasil 100-3.5-C4 4.6 ⁇ 150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) in water, and the mobile phase B was 0.05% TFA (v/v) in acetonitrile.
  • the gradient elution parameters are shown in Table 1.
  • the chromatographic column was Kromasil 300-10-C4 10 ⁇ 250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, the mobile phase A was 50 mM PBS (pH 8.0) containing 5 mM TCEP, and the mobile phase B was acetonitrile.
  • the gradient elution parameters are shown in Table 2.
  • the chromatographic column was Kromasil 300-10-C4 10 ⁇ 250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, the mobile phase A was 50 mM PBS (pH 8.0), and the mobile phase B was acetonitrile.
  • the gradient elution parameters are shown in Table 3.
  • Polypeptide 1, polypeptide 2, polypeptide 3, polypeptide 4, polypeptide 5, polypeptide 6, polypeptide 7, polypeptide 8, polypeptide 9, polypeptide 10, polypeptide 11, polypeptide 12, polypeptide 13, polypeptide 14 and polypeptide 15 were prepared according to the following method.
  • the amino acid sequences of polypeptide 1 to polypeptide 15 are shown in SEQ ID NO: 1-15, respectively.
  • MBHA resin (Xi’an Lanxiao Technology New Materials Co., Ltd., catalog number: 09-191010), with a substitution value (SD) of 0.29 mmol/g.
  • the protected amino acids are: Fmoc-Ser(tBu)-OH (CAS: 71989-33-8), Fmoc-Pro-OH (CAS: 71989-31-6), Fmoc-Ala-OH (CAS: 35661-39-3 ), Fmoc-Gly-OH (CAS: 29022-11-5), Fmoc-Leu-OH (CAS: 35661-60-0), Fmoc-Trp (Boc)-OH (CAS: 143824-78-6), Fmoc-Gln(Trt)-OH(CAS: 132327-80-1), Fmoc-Val-OH (CAS: 68858-20-8), Fmoc -Phe-OH(CAS: 35661-40-6), Fmoc-Lys(Boc)-OH(CAS: 71989-26-9), Fmoc-Glu(OtBu)-OH(CAS: 71989-18-9), Fmoc-Cys(Trt)-OH(CAS: 103213-
  • Synthesis reagents HOBt, DIC, DMF, DCM, piperidine.
  • the resin peptide was dried under vacuum and weighed.
  • the crude polypeptide was purified according to RP-HPLC purification method A, and samples with a purity of more than 90% were combined and verified by LC-MS mass spectrometry.
  • the theoretical value m/z and the measured value m/z are shown in Table 4.
  • the synthetic materials are: Fmoc-Lys(Alloc)-OH (CAS: 146982-27-6), Fmoc-AEEA-OH (CAS: 166108-71-0), Fmoc-Glu-OtBu (CAS: 84793-07-7), and octadecanediolatoic acid mono-tert-butyl ester (CAS: 843666-40-0).
  • Synthesis reagents HOBt, DIC, DMF, DCM, PIP, DIEA.
  • the reaction was carried out at room temperature for 1 hour, and the resin was removed by filtration.
  • the filtrate was rotary evaporated at 40°C to remove TFA as much as possible, and the modifier was precipitated with 7-10 times the volume of ice ether relative to the cleavage reagent, placed in a -20°C refrigerator for 20 minutes, centrifuged, and vacuum dried to obtain the modifier.
  • Dissolve polypeptide 1 in water adjust the pH to 7-8 with saturated ammonium bicarbonate (the concentration of polypeptide 1 is 2 mg/ml), dissolve C18 diacid-AEEA-gGlu-gGlu-Lys( ⁇ -bromoacetyl)-COOH with saturated ammonium bicarbonate to make the concentration of C18 diacid-AEEA-gGlu-gGlu-Lys( ⁇ -bromoacetyl)-COOH be 10 mg/mL, add C18 diacid-AEEA-gGlu-gGlu-Lys( ⁇ -bromoacetyl)-COOH solution to polypeptide 1 solution at a molar ratio of 3:1 between C18 diacid-AEEA-gGlu-gGlu-Lys( ⁇ -bromoacetyl)-COOH and polypeptide 1, react at room temperature for 0.5-1h, monitor according to RP-HPLC analysis method, and obtain a reaction solution.
  • reaction solution was purified according to RP-HPLC purification method B, and samples with a purity of more than 90% were combined and freeze-dried.
  • incretin analogs 2 to 42 incretin analogs 2 to 42, incretin analog 59, incretin analog 60, incretin analog 65, incretin analog 66, incretin analog 72 to incretin analog 84 were prepared and characterized.
  • the theoretical value m/z and the measured value m/z of each incretin analog are shown in Table 5.
  • Example 4 Determination of in vitro activity of incretin analogs by time-resolved fluorescence energy transfer (TR-FRET)
  • cAMP Hunter TM CHO-K1 GIPR Gs Cell Line (eurofins DiscoverX, catalog number: 95-0146C2) and GLP-1R-CRE-bla CHO-K1 (Life Technologies, catalog number: K1783) cell lines were used, and Tirzepatide was used as a positive control to measure the in vitro cell activity of the samples to be tested (peptides, incretin analogs). Tirzepatide can specifically bind to GIPR and GLP-1R on the cell surface, leading to the activation of membrane adenylate cyclase and the formation of cyclic adenosine monophosphate (cAMP) in the cell. The amount of cAMP generated is positively correlated with the concentration of Tirzepatide.
  • cAMP cyclic adenosine monophosphate
  • the amount of intracellular cAMP generated can be accurately determined by time-resolved fluorescence resonance energy transfer immunoassay (TR-FRET).
  • TR-FRET time-resolved fluorescence resonance energy transfer immunoassay
  • the detection kit is the LANCE UltracAMP Kit of PerkinElmer.
  • the experimental data were analyzed using Prism5 software, with sample concentration as the X-axis and the corresponding fluorescence ratio as the Y-axis.
  • a four-parameter equation was used for fitting, and the dose-response curves of the positive control and the sample to be tested were drawn to calculate the EC 50 value.
  • the EC 50 ratios of the samples and the positive control are shown in Table 6.
  • mice were fasted 2h before administration. Tirzepatide or incretin analogs were injected subcutaneously in the abdomen of each administration group, with an injection volume of 10mL/kg. The normal control group was injected with an equal volume of normal saline. The day of administration was D0. The mice were weighed and recorded every day, and the weight change rate was calculated. Starch solution (10.6g/kg, calculated according to the average weight of mice) was given 71h after administration. Blood was collected from the tail tip of the mice, and blood sugar was measured about 4.5h before administration and 72h after administration with a blood glucose meter, and the blood sugar change rate of each group of mice was calculated.
  • Body weight change rate (%) (Dt body weight - D0 body weight) / D0 body weight ⁇ 100%, wherein Dt body weight is the body weight on Dt, and D0 body weight is the body weight on D0.
  • the body weight change rate of mice is shown in Figures 1 and 2.
  • the formula for calculating blood sugar change rate is as follows:
  • Blood sugar change rate (%) (blood sugar increase value of normal control group - blood sugar increase value of each drug administration group) / blood sugar increase value of normal control group ⁇ 100%.
  • mice The blood glucose change rates of mice are shown in Table 8.
  • Example 6 In vivo pharmacokinetic evaluation in beagle dogs
  • Beagle dogs (Nanjing Yadong Experimental Animal Research Center) (weight 10-13kg) were randomly divided into groups, 3 in each group, and administered with a dose of 10nmol/kg by subcutaneous injection. Blood was collected from the eye socket within 30min before administration and 0.5, 1, 2, 4, 8, 10, 24, 48, 72, 96, 120, 144, and 168h after administration to prepare the plasma samples to be tested.
  • Example 7 Pharmacodynamic evaluation in a type 2 diabetes mouse model
  • mice from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.
  • 25 SPF db/db mice were housed in an animal laboratory at 20-26°C with alternating light and dark for 12 hours each, with free access to water and food, and were randomly divided into 4 groups before the experiment, with 5 mice in each group.
  • the specific grouping and dosing regimen are shown in Table 10.
  • Each treatment group received a subcutaneous injection of Semaglutide or incretin analogs in the abdomen with an injection volume of 2 mL/kg, and the normal control group received an injection of the same volume of PBS.
  • the day of administration was D1, and the drug was administered once every 3 days for 60 consecutive days.
  • Blood sugar was measured before the first and second administrations, 48h and 72h after administration, and blood sugar was measured 72h after each subsequent administration, and blood sugar was measured 48h after the last administration (i.e. D60).
  • Example 8 In vivo pharmacodynamic evaluation in diet-induced obese (DIO) mice
  • mice Twenty SPF DIO mice (from Shanghai Model Organisms Science Co., Ltd.) were housed in an animal laboratory at 20-26°C with alternating light and dark for 12 hours each, with free access to water and food, and were randomly divided into 4 groups before the experiment, with 4 mice in each group.
  • the specific grouping and dosing regimen are shown in Table 11.
  • Each treatment group was injected subcutaneously with Semaglutide or incretin analogs at a volume of 2 mL/kg, and the normal control group was injected with the same volume of PBS.
  • the drug was administered once every 3 days, with the day of administration being D1, for 46 consecutive days.
  • body weight was measured every 3 days. The weight change rate was calculated as follows:
  • Body weight change rate (%) (Dt body weight - D0 body weight) / D0 body weight ⁇ 100%, wherein Dt body weight is the body weight on Dt, and D0 body weight is the body weight on D0.

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Abstract

L'invention concerne des analogues d'incrétine et leur procédé de préparation, et une utilisation. Les analogues d'incrétine comprennent des polypeptides et des substituants. L'invention concerne également une composition pharmaceutique comprenant les analogues d'incrétine, un procédé de préparation des analogues d'incrétine, et une utilisation des analogues d'incrétine dans le traitement de maladies. Les analogues d'incrétine fournis ont une activité agoniste de GIPR et GLP-1 R, sont des agonistes à double récepteur, et ont des effets significatifs en termes de traitement du diabète, de diminution du sucre sanguin et de réduction du poids corporel.
PCT/CN2024/087112 2023-04-11 2024-04-11 Analogues d'incrétine et leur procédé de préparation, et utilisation Pending WO2024213022A1 (fr)

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