WO2023207106A1 - Co-agoniste du récepteur de glp-1/gip, composition pharmaceutique le comprenant et son utilisation - Google Patents

Co-agoniste du récepteur de glp-1/gip, composition pharmaceutique le comprenant et son utilisation Download PDF

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WO2023207106A1
WO2023207106A1 PCT/CN2022/137119 CN2022137119W WO2023207106A1 WO 2023207106 A1 WO2023207106 A1 WO 2023207106A1 CN 2022137119 W CN2022137119 W CN 2022137119W WO 2023207106 A1 WO2023207106 A1 WO 2023207106A1
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ser
ala
pro
ile
lys
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吕佩
田长麟
郑勇
吴文奎
王辉
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苏州星洲生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—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
    • A61P3/08—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
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • 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 a GLP-1/GIP receptor co-agonist, pharmaceutical compositions containing the same, and uses and methods for treating and/or preventing metabolic diseases or disorders.
  • Glucagon-like peptide GLP-1 is a polypeptide hormone secreted by the intestine after food stimulation. GLP-1 stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner. GLP-1 receptors are widely distributed in multiple organs or tissues throughout the body, including the central nervous system, gastrointestinal tract, cardiovascular system, liver, adipose tissue, muscle, etc. in addition to the pancreas. GLP-1 receptor agonists exert hypoglycemic effects through multiple mechanisms such as slowing gastric emptying, central appetite suppression, and reducing food intake. However, natural GLP-1 is easily degraded by dipeptidyl peptidase and loses activity in the body. Its half-life in the body is only 1-2 minutes, which greatly limits its clinical application.
  • Glucose-dependent insulinotropic hormone GIP (glucose-dependent insulinotropic) is currently believed to be mainly secreted by enteroendocrine K cells in the duodenum and upper jejunum. Similar to GLP-1, GIP stimulates insulin secretion.
  • the GIP receptor GIPR is widely distributed in the body and is expressed in the pancreas, stomach, small intestine, adipose tissue, heart, and brain tissue. In addition, activating the GIP-GIPR pathway can also exert a weight loss effect.
  • the biological activity half-life of GIP in the body is short, less than 2 minutes in mice, 7 minutes in normal people and 5 minutes in patients with type II diabetes.
  • Glucagon is a hormone produced in the ⁇ -cells of the pancreas. It acts on the liver under stress conditions such as cold and hunger to decompose glycogen in the liver and increase blood sugar. In addition to its blood sugar-raising effect, GCG also has the effects of promoting lipolysis, fat oxidation, and heating in the body (see Diabetologia, 2017, 60, 1851–1861). Long-term administration can show weight loss effects by increasing energy metabolism. , but these beneficial effects of GCG on energy metabolism have not been widely used due to its inherent blood glucose effect.
  • GLP-1 receptor agonists and GIP receptor agonists can exert the same biological effects as natural GLP-1 and GIP, and can also avoid degradation and lose activity, thus extending the duration of action.
  • GLP-1 receptor agonists particularly co-agonists with co-agonism at GLP-1 receptors and GIP receptors.
  • a co-agonist with co-agonistic properties it is desired that the agonist has a good blood glucose lowering effect, especially a simultaneous blood glucose lowering and weight loss effect. It is also desirable that the agonist has high plasma stability and thus pharmacokinetic characteristics that support once-weekly subcutaneous administration in humans.
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
  • L 1 is a peptide analog of the GIP (1-28) peptide, said L 1 is a peptide consisting of 28 amino acids, and the amino acid sequence of said L 1 is at least 39% identical to SEQ ID NO: 1,
  • L 2 is a peptide having the amino acid sequence consisting of SEQ ID NO:2,
  • n is any integer from 2 to 6
  • the compound has GLP-1 receptor agonist activity, GIP receptor agonist activity, or both.
  • the obtained compound of formula I unexpectedly maintains high activity on GLP-1 receptors and even has co-agonism on GLP-1 receptors and GIP receptors, providing Effective in lowering blood sugar and reducing weight.
  • the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:
  • the resulting compound of Formula II unexpectedly retains co-agonism at GLP-1 receptors and GIP receptors, providing hypoglycemic and weight loss effects.
  • the compound of formula II has a long half-life, supporting the pharmacokinetic profile of once-weekly subcutaneous injection in humans, which is superior to known drugs administered once-daily subcutaneous injection, thereby improving patient compliance.
  • the adverse gastrointestinal irritation of the compounds according to the present disclosure is mild and controllable, so the therapeutic effect can be improved by increasing the dosage.
  • the present disclosure provides a pharmaceutical composition comprising:
  • the present disclosure provides the use of a pharmaceutical composition according to the present disclosure or a compound according to the present disclosure or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of metabolic diseases or disorders .
  • the present disclosure provides a method of treating and/or preventing a metabolic disease or disorder, comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition according to the present disclosure or a compound according to the present disclosure or a pharmaceutical composition thereof. Acceptable salt.
  • Figure 1 is a mass spectrum of compound NBB-T007 according to the present disclosure.
  • Figure 2 is a high performance liquid chromatogram of compound NBB-T007 according to the present disclosure.
  • Figure 3 is a potency-concentration curve of semaglutide acting on the target as a control.
  • Figure 4 is a potency-concentration curve of compound NBB-T007-1 acting on a target according to the present disclosure.
  • Figure 5 is a potency-concentration curve of compound NBB-T007-2 acting on a target according to the present disclosure.
  • Figure 6 is a potency-concentration curve of compound NBB-T007-3 acting on a target according to the present disclosure.
  • Figure 7 is a potency-concentration curve of compound NBB-T007-4 acting on a target according to the present disclosure.
  • Figure 8 is a potency-concentration curve of compound NBB-T007-5 acting on a target according to the present disclosure.
  • Figure 9 is a potency versus concentration curve of compound NBB-T007-6 acting on a target according to the present disclosure.
  • Figure 10 is a potency versus concentration curve of compound NBB-T007-7 acting on a target according to the present disclosure.
  • Figure 11 is a potency-concentration curve of compound NBB-T007-8 acting on a target according to the present disclosure.
  • Figure 12 is a potency versus concentration curve of compound NBB-T007-9 acting on a target according to the present disclosure.
  • Figure 13 is a potency versus concentration curve of compound NBB-T007-10 acting on a target according to the present disclosure.
  • Figure 14 is a potency versus concentration curve of compound NBB-T007-11 acting on a target according to the present disclosure.
  • Figure 15 is a potency versus concentration curve of compound NBB-T007-12 acting on a target according to the present disclosure.
  • Figure 16 is a potency versus concentration curve of compound NBB-T007-14 acting on a target according to the present disclosure.
  • Figure 17 is a potency versus concentration curve of compound NBB-T007-15 acting on a target according to the present disclosure.
  • Figure 18 is a potency versus concentration curve of compound NBB-T007 acting on a target according to the present disclosure.
  • Figure 19 is a potency versus concentration curve of compound NBB-T007-17 acting on a target according to the present disclosure.
  • Figure 20 is a potency versus concentration curve of compound NBB-T007-18 acting on a target according to the present disclosure.
  • Figure 21 is a potency versus concentration curve of compound NBB-T007-19 acting on a target according to the present disclosure.
  • Figure 22 is a potency versus concentration curve of compound NBB-T007-21 acting on a target according to the present disclosure.
  • Figure 23 is a potency versus concentration curve of compound NBB-T007-22 acting on a target according to the present disclosure.
  • Figure 24 is a potency versus concentration curve of compound NBB-T007-23 acting on a target according to the present disclosure.
  • Figure 25 is a potency versus concentration curve of compound NBB-T007-24 on a target according to the present disclosure.
  • Figure 26 is a potency versus concentration curve of compound NBB-EX4 on a target according to the present disclosure.
  • Figure 27 is the blood glucose-time change curve of the db/db mice tested.
  • Figure 28 is the body weight-time change curve of the db/db mice tested.
  • Figure 29 is the blood glucose reduction percentage-time curve of the db/db mice tested.
  • Figure 30 is the blood glucose-time change curve of normal mice tested.
  • Figure 31 is a body weight-time change curve of normal mice tested.
  • Figure 32 is a concentration-time change curve in plasma of the compound NBB-T007 according to the present disclosure injected subcutaneously in the test SD rats.
  • Figure 33 is a concentration-time change curve of semaglutide in plasma injected subcutaneously as a control in SD rats.
  • Figure 34 is a concentration-time change curve in plasma of NBB-T007-10 according to the present disclosure injected subcutaneously into SD rats.
  • Figure 35 is a concentration-time change curve in plasma of NBB-T007-12 according to the present disclosure injected subcutaneously in SD rats.
  • Figure 36 is the body weight-time change curve of the DIO mice tested.
  • Figure 37 is the blood glucose-time change curve of the DIO mice tested.
  • Figure 38 is the blood glucose-time change curve of the DIO mice tested.
  • Figure 39(a) is a bar graph showing changes in serum insulin content of DIO mice.
  • Figure 39(b) is a histogram of changes in serum biochemical indicators (UREA, TG, CHO, HDL, LDL and CREA) of the DIO mice tested.
  • Figure 39(c) is a histogram of changes in serum biochemical indicators (ALT, AST, ALB and TBIL) of the DIO mice tested.
  • Figure 40(a) is a bar graph showing changes in body fat percentage of DIO mice tested.
  • Figure 40(b) is a bar graph showing changes in triglyceride content in DIO mice.
  • analog means a compound, such as a natural or synthetic peptide or polypeptide, that activates a target receptor and elicits at least one in vivo or in vitro effect of an agonist on that receptor.
  • sequence or structural formula of a compound contains the standard one-letter or three-letter codes for the 20 natural amino acids that make up proteins (also known as proteinogenic amino acids or encoded amino acids). Except for proline (Pro), the amino and carboxyl groups of the remaining 19 protein amino acids are connected to the ⁇ carbon atom, also known as ⁇ -amino acids.
  • ⁇ -Ala represents ( ⁇ -)alanine, with the structure CH 3 CH(NH 2 )COOH, in which the amino group is attached to the ⁇ carbon atom.
  • ⁇ -Ala represents ⁇ -alanine, and its structural formula is NH 2 CH 2 CH 2 COOH, in which the amino group is connected to the ⁇ carbon atom.
  • each amino acid residue can be in the L-configuration or the D-configuration independently of each other, and can also have pendant substituents on the carbon atoms independently of each other.
  • a compound may also contain unnatural amino acid residues in its sequence or structural formula.
  • Aib represents 2-aminoisobutyric acid residue
  • homo-Phe represents homophenylalanine residue
  • Cpa-Ala represents p-chlorophenylalanine residue
  • Fpa5-Ala represents pentafluorophenylalanine Residue
  • Na1 represents 1-naphthylalanine residue.
  • the position numbering of amino acids is calculated from the leftmost N-terminus of the peptide chain or structural formula of the compound.
  • the N-terminal amino acid is tyrosine (Tyr) at position 1
  • the C-terminal amino acid is serine (Ser) at position 39.
  • the -NH-( CH2 ) 4 -C(O)- unit is not a residue of the natural alpha-amino acid, nor is it 2 amino acid residues, but only 1 amino acid residue.
  • the -NH-( CH2 ) 4 -C(O)- units are formally numbered herein as occupying 2 positions at amino acid positions 29 and 30.
  • an "individual in need thereof” means a mammal, preferably a human, but also a non-human animal, including non-human primates (e.g., monkeys), having a condition, disease, disorder or symptom in need of treatment or prevention. , cynomolgus monkeys, etc.), pets (such as cats, dogs, etc.), livestock (such as cattle, sheep, pigs, horses, etc.) and rodents (such as rats, mice, guinea pigs, etc.).
  • non-human primates e.g., monkeys
  • pets such as cats, dogs, etc.
  • livestock such as cattle, sheep, pigs, horses, etc.
  • rodents such as rats, mice, guinea pigs, etc.
  • an "effective amount” means one that provides the desired effect (i.e., can produce a clinically measurable difference in the condition of the individual) in the individual being diagnosed or treated upon administration of single or multiple doses to an individual in need thereof. , such as, for example, a reduction in blood glucose, and/or a reduction in weight or fat), an amount, concentration, or dose of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof. Effective amounts are readily determined by those skilled in the art using known techniques and by observation of results obtained under similar circumstances.
  • determining the amount effective for an individual many factors are considered, including, but not limited to, the species of the mammal, size, age, general health, the specific disease or condition involved, the severity of the disease or condition, the individual's response, The specific compound administered, the mode of administration, the bioavailability characteristics of the formulation administered, the dosage regimen selected, the use of concomitant drug therapy, and other relevant circumstances.
  • treating means attenuating, inhibiting, reversing, slowing or stopping the progression or severity of an existing condition, disease, disorder or symptom.
  • C 12 -C 24 aliphatic diacid means a linear or branched dicarboxylic acid having 12 to 24 carbon atoms.
  • C 12 -C 24 aliphatic diacids suitable for the present disclosure may be saturated or unsaturated diacids, with saturated diacids being preferred.
  • C12 - C24 fatty acids suitable for compounds of the present disclosure include, but are not limited to, dodecanedioic acid ( C12dioic acid), tridecanedioic acid ( C13dioic acid), tetradecanedioic acid ( C14dioic acid).
  • plasma half-life or “half-life” refers to the time required for half of the compound of interest to be cleared from the plasma.
  • in vitro activity refers to an indicator of a peptide's ability to activate GLP-1 receptors, GIP receptors, and/or GCG receptors in cell-based assays. In vitro activity is expressed as the "half maximal effective concentration ( EC50 )", which is the effective concentration of compound that results in 50% activity in a single dose response experiment. As used herein, “ EC50” means the effective concentration of a compound that results in 50% activation/stimulation of an assay endpoint, such as a dose-response curve (eg, cAMP).
  • EC50 half maximal effective concentration
  • semaglutide refers to a chemically synthesized GLP-1 analog having the structure shown below:
  • Tirzepatide is a GLP-1/GIP receptor co-agonist.
  • L 1 is a peptide analog of the GIP (1-28) peptide, said L 1 is a peptide consisting of 28 amino acids, and the amino acid sequence of said L 1 is at least 39% identical to SEQ ID NO: 1,
  • L 2 is a peptide having the amino acid sequence consisting of SEQ ID NO:2,
  • n is any integer from 2 to 6
  • the compound has GLP-1 receptor agonist activity, GIP receptor agonist activity, or both.
  • SEQ ID NO:1 is the GIP (1-28) sequence: YAEGTFISDYSIAMDKIHQQDFVNWLLA, namely Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile -His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala.
  • SEQ ID NO:2 is PSSGAPPPS, which is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.
  • the amino acid sequence of L 1 has identical amino acids at a total of 11, 18, 19, or 20 positions compared to SEQ ID NO: 1.
  • the amino acid sequence of L 1 is at least 39% identical to SEQ ID NO: 1, for example, has 39%, 43%, 46%, 50%, 54%, 57%, 61%, 64% , 68%, 71%, 75%, 79%, 82%, 86%, 89%, 93%, 96% or 100% identical.
  • amino acid sequence of L 1 is 39%, 64%, 68%, or 71% identical to SEQ ID NO:1.
  • n 2, 3, 4, 5 or 6, with 4 being preferred.
  • the resulting compound of formula I can unexpectedly maintain agonism on GIP receptors, and even have co-agonism on GLP-1 receptors and GIP receptors, providing reduced Efficacy in blood sugar and weight loss.
  • L 1 contains a Y1H substitution compared to SEQ ID NO: 1.
  • L 1 compared to SEQ ID NO: 1, includes a substitution selected from A2G, A2(Aib), and A2( ⁇ -Ala).
  • L 1 contains a T5S substitution compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from F6 (homo-Phe) and F6 (Cpa-Ala) compared to SEQ ID NO: 1.
  • L 1 contains an I7T substitution compared to SEQ ID NO: 1.
  • L 1 compared to SEQ ID NO: 1, includes a substitution selected from Y10L and Y10(Fpa5-Ala).
  • L 1 contains a I12K substitution compared to SEQ ID NO: 1.
  • L 1 compared to SEQ ID NO: 1, includes a substitution selected from A13Q, A13(Aib), and A13Y.
  • L 1 includes a substitution selected from M14L and M14( ⁇ -meL) compared to SEQ ID NO: 1.
  • L 1 contains a D15E substitution compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from K16E and K16(Ala) compared to SEQ ID NO: 1.
  • L 1 contains an I17E substitution compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from H18A and H18(Aib) compared to SEQ ID NO:1.
  • L 1 contains the Q19V substitution compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from Q20R and Q20K when compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from D21L, D21A, D21E, and D21(Abu) compared to SEQ ID NO:1.
  • L 1 includes a substitution selected from V23I and V23L compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from N24E and N24Q compared to SEQ ID NO: 1.
  • L 1 includes a substitution selected from W25(Na1) and W25(2-me-Trp) compared to SEQ ID NO:1.
  • L 1 includes a substitution selected from L27K and L27I compared to SEQ ID NO: 1.
  • L 1 contains an A28N substitution compared to SEQ ID NO: 1.
  • the resulting compound of formula XXI unexpectedly retains agonism at the GLP-1 receptor, providing hypoglycemic and weight loss effects.
  • the amino acid at position 16 or 20 is lysine (Lys)
  • the C 12 -C 24 aliphatic diacid is conjugated to the acid via a direct bond or via a linker.
  • the ⁇ -amino group of the lysine (Lys) side chain is chemically modified, and the linker is selected from (AEEA) 2 -( ⁇ -Glu) a , AEEA-Ahx-( ⁇ -Glu) a , (Ahx) 2 - ( ⁇ -Glu) a and ( ⁇ -Ala) 2 -( ⁇ -Glu) a , where a is 1 or 2;
  • the chemical modification is carried out by conjugating eicosanedioic acid to the ⁇ -amino group of the lysine (Lys) side chain at position 16 or 20 via (AEEA) 2 -( ⁇ -Glu); or
  • Eicosanedioic acid is conjugated to lysine 20 ( Lys) side chain of the ⁇ -amino group is chemically modified.
  • histidine (His) or tyrosine (Tyr) at position 1 is amidated, e.g., linked to by -C m H 2m+1 -C(O)- On the amino group of the histidine (His) or tyrosine (Tyr), and m is an integer from 1 to 20;
  • the amino group of tyrosine (Tyr) at position 1 is amidated by being connected to CH 3 -C(O) or to C 19 H 39 -C(O)-.
  • the ⁇ -carbon atoms of any two amino acids can be connected to form a ring via a direct bond or via a linker selected from an alkyl or alkenyl group containing 2 to 20 carbon atoms. base;
  • the amino acids at positions 13 and 16 are both alanine
  • the ⁇ -carbon atom of alanine (Ala) at position 13 and alanine at position 16 are connected via an alkenyl group containing 10 carbon atoms.
  • the ⁇ -carbon atoms of (Ala) are attached.
  • the resulting compound of Formula II unexpectedly retains co-agonism at GLP-1 receptors and GIP receptors, providing hypoglycemic and weight loss effects.
  • the compound of formula II has a long half-life, supporting the pharmacokinetic profile of once-weekly subcutaneous injection in humans, which is superior to known drugs administered once-daily subcutaneous injection, thereby improving patient compliance.
  • X is an amino acid residue selected from 2 -aminoisobutyric acid (Aib) and ( ⁇ -Ala),
  • X 5 is an amino acid residue selected from Thr and Ser
  • X 6 is an amino acid residue selected from Phe, homophenylalanine (homo-Phe) and p-chlorophenylalanine (Cpa-Ala),
  • X 10 is an amino acid residue selected from Tyr and pentafluorophenylalanine (Fpa5-Ala),
  • X 12 is an amino acid residue selected from Ile and Lys,
  • X 13 is an amino acid residue selected from 2-aminoisobutyric acid (Aib), Tyr and Ala,
  • X 16 is an amino acid residue selected from Lys and Ala,
  • X 18 is an amino acid residue selected from Ala and Aib,
  • X 21 is an amino acid residue selected from Ala, Glu and 2-aminobutyric acid (Abu),
  • X 23 is an amino acid residue selected from Val and Leu,
  • X 24 is an amino acid residue selected from Gln and Asn, and
  • X 25 is an amino acid residue selected from Trp, 2-methyltryptophan (2-me-Trp) and 1-naphthylalanine (Nal).
  • the compound has a structure selected from any one of Formula III below to Formula XX below:
  • each amino acid residue is in the L-configuration or the D-configuration independently of one another.
  • each amino acid residue is in the L-configuration independently of one another.
  • any one of Formulas I to XXI there is at least 1 D-configured amino acid residue, such as 1-5, such as 1 or 2 D-configured amino acid residues.
  • base such as D-Glu, D-Thr, D-Phe and/or D-Ala, etc.; the remaining amino acid residues are in L-configuration.
  • the amino acid at position 3 is L-Glu or D-Glu.
  • the amino acid at position 5 is L-Thr or D-Thr.
  • the amino acid at position 6 is L-Phe or D-Phe.
  • the amino acid at position 35 is L-Ala or D-Ala.
  • the carbon atoms of each amino acid residue can have pendant substituents independently of each other.
  • the substituents are each independently selected from linear, branched or cyclic, saturated or unsaturated aliphatic groups, or aromatic groups.
  • the substituents may be further substituted.
  • the substituent is, for example, C 1 -C 20 alkyl, such as methyl; C 2 -C 20 alkenyl, such as pentenyl or deenyl; substituted or unsubstituted phenyl, such as p- Chlorophenyl, pentafluorophenyl; and/or substituted or unsubstituted condensed ring aryl, such as 1-naphthyl.
  • Substituted amino acid residues include leucine residues in which the ⁇ carbon atom is replaced by methyl group ( ⁇ -meL), tryptophan residues in which the 2-position carbon atom is replaced by methyl group (2-me-Trp), and p-chlorophenyl-substituted alanine residue (Cpa-Ala), and pentafluorophenyl-substituted alanine residue (Fpa5-Ala).
  • the amino acid at position 14 is a leucine residue in which the alpha carbon atom is replaced with a methyl group ( ⁇ -meL).
  • the amino acid at position 25 is a tryptophan residue in which the 2-carbon atom is replaced by a methyl group (2-me-Trp).
  • C 12 -C 24 aliphatic diacid conjugated to an amino acid refers to any natural or unnatural amino acid that has the ability to bind by covalent bond, or preferably by linker.
  • a functional group conjugated to the aliphatic diacid examples include amino, carboxyl, chlorine, bromine, iodine, azide, alkynyl, alkenyl and thiol, with amino being preferred.
  • Examples of natural amino acids including such functional groups include lysine K (having an amino group), cysteine C (having a thiol group), glutamic acid E (having a carboxyl group), and aspartic acid D (having a carboxyl group).
  • the conjugated amino acid is lysine K.
  • conjugation refers to conjugation to the epsilon-amino group of the K side chain of lysine.
  • the conjugation is acylation.
  • compounds of the invention include an aliphatic diacid moiety conjugated to the epsilon-amino group of the K side chain of lysine at position 16 or 20 via a linker.
  • compounds of the invention include an aliphatic diacid moiety that is conjugated directly, without a linker, to a natural or non-natural amino acid with functional groups available for conjugation.
  • any of Formula II to Formula XX at the lysine (Lys) at position 16 or 20, a C 12 -C 24 aliphatic diacid is added via a direct bond or via a linker Conjugated to the ⁇ -amino group of the lysine (Lys) side chain for chemical modification, the linker is selected from (AEEA) 2 -( ⁇ -Glu) a , AEEA-Ahx-( ⁇ -Glu) a , (Ahx) 2 -( ⁇ -Glu) a and ( ⁇ -Ala) 2 -( ⁇ -Glu) a , where a is 1 or 2, endow the compound with excellent in vivo and in vitro activity.
  • the linker is selected from (AEEA) 2 -( ⁇ -Glu), AEEA-Ahx-( ⁇ -Glu), (Ahx) 2 -( ⁇ -Glu), and ( ⁇ -Ala) 2 -( ⁇ - Glu).
  • AEEA is an abbreviation for [2-(2-amino-ethoxy)-ethoxy]-acetyl, which means [2-(2-amino-ethoxy)-ethoxy]-acetyl. .
  • ⁇ -Glu represents ⁇ -glutamyl.
  • Ahx is the abbreviation of amino hexanoyl, which means aminocaproyl.
  • ⁇ -Ala represents ⁇ -alanyl group.
  • any one of Formula II to Formula XX via the linker (AEEA) 2 -( ⁇ -Glu), AEEA-Ahx-( ⁇ -Glu), (Ahx) 2 -( ⁇ -Glu ) or ( ⁇ -Ala) 2 -( ⁇ -Glu), by conjugating octadecanedioic acid or eicosanedioic acid to the ⁇ -amino group of the lysine (Lys) side chain at position 16 or 20 Perform chemical modifications.
  • eicosanedioic acid is conjugated to lysine (Lys) at position 20 via (AEEA) 2 -( ⁇ -Glu) Chemical modification of the ⁇ -amino group of the side chain.
  • chemical modification is performed by conjugating eicosanedioic acid to the epsilon-amino group of the lysine (Lys) side chain at position 16 via (AEEA) 2- ( ⁇ -Glu).
  • chemical modification occurs by conjugating eicosanedioic acid to the epsilon-amino group of the lysine (Lys) side chain at position 20 via (Ahx) 2- ( ⁇ -Glu).
  • eicosanedioic acid is chemically modified by conjugating eicosanedioic acid to the epsilon-amino group of the lysine (Lys) side chain at position 20 via AEEA-Ahx-( ⁇ -Glu).
  • the chemistry is performed by conjugating eicosanedioic acid to the epsilon-amino group of the lysine (Lys) side chain at position 20 via ( ⁇ -Ala) 2- ( ⁇ -Glu) Grooming.
  • the amino group of [2-(2-amino-ethoxy)-ethoxy]-acetyl (AEEA) unit is connected, and one terminal carboxyl group of eicosanedioic acid (C 20 diacid) removes the hydroxyl group to obtain the terminal acyl group , and is connected to the amino group of ⁇ -glutamyl ( ⁇ -Glu) via the terminal acyl group, thereby chemically modifying the ⁇ -amino group of the lysine (Lys) side chain at position 20.
  • the use of a linker to conjugate a C 12 -C 24 aliphatic diacid to the epsilon-amino group of the lysine (Lys) side chain of compounds of Formulas I to XXI helps provide the compounds with GLP-1 receptors and GIP receptors, and offers the potential to generate long-acting compounds.
  • the histidine (His) or tyrosine (Tyr) at position 1 is amidated, for example, by- C m H 2m+1 -C(O)- is linked to the amino group of the histidine (His) or tyrosine (Tyr) for amidation, and m is an integer from 1 to 30.
  • m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29 or 30.
  • m is 1 or 19.
  • the amino group of tyrosine (Tyr) at position 1 is amidated by being connected to CH 3 -C(O)- or to C 19 H 39 -C(O)-, respectively, as in the following compounds T007-19 (acetylation) and T007-20 (eicosanoylation) are shown.
  • the ⁇ -carbon atoms of any two amino acids can be connected to form a ring via a direct bond or via a linker selected from the group consisting of 2 to 20 Alkyl or alkenyl group of carbon atoms.
  • This side chain modification is also called "staple peptide" modification, which is used to enhance the structural rigidity of the polypeptide and stabilize the activity of the polypeptide compound.
  • the linking group is an alkenyl group containing 2 to 20 carbon atoms
  • the linking group can be introduced by using a Grubbs catalyst.
  • the ring-forming ⁇ -carbon atoms may come from the side chains of two adjacent amino acids or from the side chains of two amino acids separated by at least 1 amino acid.
  • the linking group is an alkyl group containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms or alkenyl.
  • the linker is an alkenyl group containing 10 carbon atoms.
  • the alpha-carbon atom of alanine (Ala) at position 13 is connected to the alpha-carbon atom of alanine (Ala) at position 16 via an alkenyl group containing 10 carbon atoms. .
  • the side chain carboxyl group of aspartic acid (Asp) or glutamic acid (Glu) is in contact with lysine (Lys), arginine (Arg) Or the side chain amino group of histidine (His) can form a ring by forming an amide bond.
  • the side chain thiol group of cysteine Cys
  • the side chain amino group of glutamine Gln
  • the side chain imidazolyl group of histidine His
  • the side chain amino group of asparagine Asn
  • Trt trityl
  • Arg side chain guanidine group of arginine
  • Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
  • Boc tert-butoxycarbonyl protecting group, tert-butoxycarbonyl
  • Thr side chain hydroxyl group of threonine
  • phenol group of tyrosine (Tyr) are protected by tBu (tert-butyl group, tert-butyl) Protection
  • the side chain carboxyl groups of aspartic acid (Asp) and glutamic acid (Glu) are protected by O
  • compounds according to the present disclosure are prepared by a method comprising:
  • the Rink-Amide-AM resin resin previously protected by Fmoc is swollen, and then the Fmoc protecting group of the Rink-Amide-AM resin resin is removed with a solution of N,N-dimethylformamide (DMF) containing 20% piperidine.
  • DMF N,N-dimethylformamide
  • the condensation agent 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3 , 3-tetramethyluronium hexafluorophosphate, HCTU)
  • the carboxyl group of the first amino acid with Fmoc protection (from the rightmost C end) is condensed in the form of an amide bond onto the swollen and deprotected Rink-amide-AM resin.
  • N,N-dimethylformamide (DMF) solution containing 20% piperidine to remove the Fmoc protecting group on the amino group, and wash.
  • DMF N,N-dimethylformamide
  • the condensing agent HCTU is used, and the 2nd to 9th amino acids (from the rightmost C end) protected by Fmoc, 5-aminovaleric acid (Fmoc-NH-() protected by Fmoc are respectively used CH 2 ) 4 -C(O)OH), and the Fmoc-protected amino acid from position 12 to position 39 (from the rightmost C end), repeat the previous coupling reaction to form an amide bond and remove Fmoc protection in sequence. cycle of base deprotection and cleaning.
  • Fmoc-protected linker such as Fmoc-AEEA, Fmoc-Ahx, or Fmoc- ⁇ -Ala
  • HCTU condensing agent
  • Fmoc and OtBu protected glutamic acid Fmoc-Glu(OtBu)-OH
  • condensing agent HCTU
  • C 12 -C 24 aliphatic diacid or its derivative for example, monotert-butyl ester of the diacid
  • a condensing agent HCTU
  • TSA trifluoroacetic acid
  • Ton Triisopropyl silane
  • the cleavage reagent reacts with Rink-Amide-AM resin to remove the polypeptide from the resin. cleaved from the resin carrier. Precipitate from frozen ice ether to obtain the crude polypeptide solid product. The solid crude polypeptide is centrifuged, dried and crushed to obtain the purified polypeptide.
  • the purified peptides were subjected to electrospray mass spectrometry to determine the molecular structure, and high performance liquid chromatography was used to analyze the purity of the purified peptides.
  • composition comprising:
  • compositions may also contain other components, such as physiologically/pharmaceutically acceptable carriers, diluents and excipients, to facilitate administration to an individual
  • physiologically/pharmaceutically acceptable carriers such as physiologically/pharmaceutically acceptable carriers, diluents and excipients, to facilitate administration to an individual
  • the administration of the drug facilitates the absorption of the compound as the active ingredient or its pharmaceutically acceptable salt and thereby exerts biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of compounds according to the present disclosure that are safe and effective when administered in vivo and are biologically active.
  • Compounds according to the present disclosure can react with a variety of inorganic and organic acids to form pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts and common methods for preparing them are well known in the art. See, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd revised edition (Wiley-VCH, 2011); S. M. Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No.1, January 1977.
  • a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof may be formulated as a pharmaceutical composition for administration by parenteral routes (eg, subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal).
  • parenteral routes eg, subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal.
  • Such pharmaceutical compositions and methods for their preparation are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy (ed. D.B. Troy, 21st ed., Lippincott, Williams & Wilkins, 2006).
  • Pharmaceutically acceptable salts according to the present disclosure include, but are not limited to, trifluoroacetate, hydrochloride, and acetate.
  • the present disclosure provides the use of a pharmaceutical composition according to the present disclosure or a compound according to the present disclosure or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of metabolic diseases or disorders;
  • said metabolic diseases or disorders include diabetes and diabetes-related conditions, and obesity and obesity-related conditions;
  • the diabetes and diabetes-related conditions include insulin resistance, glucose intolerance, elevated fasting glucose, prediabetes, type I diabetes, type II diabetes mellitus (T2DM), gestational diabetes hypertension, dyslipidemia, atherosclerosis sclerosis, arteriosclerosis, coronary heart disease, peripheral arterial disease, and atherogenic dyslipidemia, dyslipidemia, elevated blood pressure, hypertension, prothrombotic and proinflammatory states, and combinations thereof;
  • obesity and obesity-related conditions include obesity-associated inflammation, obesity-associated gallbladder disease, obesity-induced sleep apnea, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and combinations thereof.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • drugs of the present disclosure are used to treat type II diabetes.
  • the present disclosure provides a method of treating and/or preventing a metabolic disease or disorder, comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition according to the present disclosure or a compound according to the present disclosure or a pharmaceutically acceptable salt thereof .
  • the pharmaceutical composition, the compound, or a pharmaceutically acceptable salt thereof is administered to the subject by subcutaneous injection.
  • the pharmaceutical composition, the compound, or a pharmaceutically acceptable salt thereof is administered to the subject once weekly.
  • the pharmaceutical composition, the compound, or a pharmaceutically acceptable salt thereof is administered to the subject once weekly by subcutaneous injection.
  • N,N-dimethylformamide (DMF) and dichloromethane (DCM) used in this article are common reagents with a purity of 99.7%, and the excipients are 0.05% NaHCO 3 solution.
  • the 20% piperidine solution refers to the volume percentage, which can be obtained, for example, by the following method: measure 100 mL of piperidine with a graduated cylinder, and add DMF to the graduated cylinder scale of 500 mL.
  • draining the solvent means, for example, using an air pump to pump the solvent in the polypeptide synthesis tube into a filter bottle, and draining the solvent until the resin becomes dry powder.
  • step e) Repeat cleaning step c) in step (2) "Resin Deprotection".
  • the polypeptide is formed in the following way: starting from the first amino acid at the rightmost C-terminal of the polypeptide chain, and connecting the amino acids one by one toward the leftmost N-terminal.
  • step c) Cleaning: Repeat cleaning step c) in step (2) "Resin Deprotection".
  • the second to ninth amino acids are connected in sequence.
  • Fmoc-Pro is used respectively.
  • step c) Cleaning: Repeat cleaning step c) in step (2) "Resin Deprotection".
  • Ice ether precipitation and centrifugation operation Add 40 mL ice ether to the 50 mL centrifuge tube, shake the centrifuge tube appropriately, put the centrifuge tube into the centrifuge, set the speed to 3500 rpm, and centrifuge for 3 minutes; after centrifugation is completed, discard the supernatant liquid.
  • Figure 1 is an ESI-MS (electrospray mass spectrometry) characterization of the purified peptide compound NBB-T007. The peaks on the figure represent the molecular weights of different mass-to-charge ratios.
  • Figure 2 is a high performance liquid chromatogram showing that the synthesized NBB-T007 has a purity of 95%.
  • Fmoc-S5-OH (Cas No.: 288617-73-2) and Fmoc-R5 were used at the 24th and 27th positions (from the rightmost C end) respectively.
  • -OH (Cas No.: 288617-77-6) is used as the amino acid raw material.
  • Grubbs catalyst (Cas No. 172222- 30-9) into a 10mL EP tube, and then add 4mL of DCM to dissolve. After mixing evenly, transfer the mixed solution to the peptide synthesis tube.
  • Human GLP-1R receptor, GIPR receptor and GCGR receptor were cloned into pcDNA3.1 vector respectively.
  • the excitation wavelength is 340 nm, and the emission wavelengths are 620 nm and 655 nm.
  • NBB-T007 series compounds according to the present disclosure unexpectedly show activity against human GIP receptors and Dual activity of GLP-1 receptor.
  • NBB-T007-22, NBB-T007-23 and NBB-T007-24 have triple activity on human GIP receptor, GLP-1 receptor and GCG receptor.
  • Compound NBB-EX4 has high activity against human GLP-1R, indicating that by replacing two adjacent glycines at positions 29 and 30 with -CH 2 -CH 2 - units -NH-CH 2 -C(O )-NH-CH 2 -C(O)-contains peptide bonds to modify the peptide chain, which is widely applicable to peptide drugs and can maintain high activity against human GLP-1R.
  • mice Male db/db mice (Changzhou Cavins), 7-8 weeks old, each weighing 33-40 g were used.
  • the excipient control ("solvent group", 0.05% NaHCO 3 solution), the semaglutide control (dose 50 nmol/kg) dissolved in the excipient, and the NBB-T007 series compounds prepared in the previous examples ( A dose of 50 nmol/kg) was administered to db/db mice ad libitum by subcutaneous injection. Blood was collected from the tail vein using a Wenhao fast blood glucose meter (OneTouch UltraEasy, Johnson & Johnson), and the blood glucose levels of the mice were measured continuously for 48 hours. At the same time, the body weight of db/db mice was monitored at 0h, 24h and 72h. The test results are shown in the table below and Figure 27 to Figure 29.
  • Formula IV* Use a linker (AEEA-Ahx-( ⁇ -Glu)) at the 20th lysine (Lys) of formula IV to conjugate eicosanedioic acid;
  • NBB-T007 series of compounds according to the present disclosure have an obvious hypoglycemic effect that is equivalent to or better than that of semaglutide, and can maintain the pharmacodynamic effect for 48 hours; among them, compounds NBB-T007, NBB-T007-10 and NBB-T007-12 have particularly better blood sugar-lowering and weight-lowering effects.
  • mice Male db/db mice (Changzhou Cavins), 7-8 weeks old, each weighing 33-40 g were used.
  • the mice were housed individually in a temperature-controlled (22-25°C) facility with a 12-hour light/dark cycle (lighting started at 08:00) and with free access to food and water.
  • Semaglutide control dose 30 nmol/kg
  • Tirzepatide control dose 30 nmol/kg
  • excipient 0.05% NaHCO 3 solution
  • NBB-prepared in the previous examples were used respectively.
  • T007-12 compound (dose 30 nmol/kg) was administered to db/db mice ad libitum via subcutaneous injection twice a week for 12 weeks. During the administration period, the mice's weight, food intake, and blood sugar were monitored, and blood was collected at weeks 2, 4, 6, 8, and 10 for detection of glycated hemoglobin HbA1C. The test results for glycated hemoglobin inhibition (%) are shown in the table below.
  • the tested compound has a significant reducing effect on glycated hemoglobin in type II diabetic mice after long-term administration, suggesting that it can effectively improve blood sugar in db/db mice.
  • mice C57BL/6 mice (Beijing Vitong Lever), male, 7-10 weeks old, weighing 18-20g.
  • the mice were housed individually in a temperature-controlled (22-25°C) facility with a 12-hour light/dark cycle (lighting started at 08:00) and with free access to food and water. After acclimating to the facility, the mice were randomly divided into groups of 6, according to blood glucose and body weight, so that each group had a similar starting average body weight and blood glucose concentration. The mice were fasted overnight for 12-16 hours. The mice were weighed the next day, and 0-minute blood glucose was measured using a Wenhao rapid blood glucose meter (OneTouch UltraEasy, Johnson & Johnson).
  • test substances were used respectively: excipient control ("solvent group", 0.05% NaHCO 3 solution), and semaglutide control (25 nmol/kg) dissolved in the excipient and NBB prepared in the previous example -T007 series compounds (dose 25nmol/kg) were administered to C57BL/6 mice ad libitum by subcutaneous injection, and glucose solution (2g/kg) was administered intraperitoneally at the same time, and the concentrations at 15min, 30min, 60min, and 120min after administration were measured. Blood sugar level. At the same time on the second and third days, no test substance was administered, but glucose solution (2g/kg) was administered intraperitoneally, and blood glucose levels were measured at 15 min, 30 min, 60 min, and 120 min after administration. Calculate the area under the blood glucose-time curve AUC (area under the curve). Furthermore, the body weight of the mice was monitored at 24h, 48h and 72h after administration. The test results are shown in the table below and Figure 30 to Figure 31.
  • Rats (Beijing Vitong Lever) were selected, male, 8-10 weeks old, weighing 180-200g. Rats were housed individually in temperature-controlled (22-25°C) facilities with a 12-h light/dark cycle (lighting started at 08:00) and had free access to food and water. After the rats adapted to the facility, they were randomly divided into groups, with 3 rats in each group.
  • the excipient control (0.05% NaHCO 3 solution), the NBB-T007 series compounds prepared in the previous examples (dose 1 mg/kg) and semaglutide (dose 1 mg/kg) dissolved in the excipient were administered subcutaneously, At 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, 48h, and 72h after administration, 0.3 mL of venous blood was collected from the jugular vein and placed in EDTA2K anticoagulant tubes. The plasma was collected by centrifugation at 8000 rpm for 5 minutes and passed through LC- The MS/MS method is used to determine the plasma concentration of the test substance, and methanol is used to extract the compounds in the plasma sample.
  • the sample processing steps are as follows:
  • T 1/2 half-life
  • T max time to reach maximum concentration
  • C max maximum plasma concentration
  • AUC INF _obs from the beginning of administration to theory Extrapolating the AUC to time at infinity
  • MRT INF_obs is the average residence time from time zero to time at infinity.
  • compounds NBB-T007, NBB-T007-10 and NBB-T007-12 reach mean maximum plasma concentrations approximately 8 hours after subcutaneous administration.
  • the half-lives of compounds NBB-T007 and NBB-T007-12 in rats are 11.82 and 9.29 hours respectively, supporting the possibility of once-weekly administration.
  • 0.5mL of blood was taken from the forelimb vein, and EDTA- In the K2 test tube, the whole blood was collected and temporarily stored in an ice water bath, centrifuged at 11,000 rpm for 5 minutes within 30 minutes, the plasma was separated, and placed in a plasma separation refrigerator to be frozen for testing.
  • LC-MS/MS method was used to detect the concentration of prototype drug in plasma.
  • WinNonlin software to calculate relevant pharmacokinetic parameters T max , C max , AUC last , AUC 0-t (AUC from the beginning of administration to time t), AUC INF_obs (the time from the beginning of administration to theoretical extrapolation to infinity AUC), T 1/2 , CL, etc. See the table below for test results.
  • T 1/2 half-life
  • C max maximum plasma concentration
  • mice 70 male C57BL/6 mice (Nanjing Jicui Yaokang) were selected.
  • the animal room environment was maintained at a temperature of 23 ⁇ 2°C, a humidity of 40-70%, and 12 hours of light and dark alternating (lighting started at 08:00).
  • 4-5 mice were kept in each cage, and the bedding was changed twice a week.
  • the mice were fed high-fat feed (60% Kcal fat, D12492) for 10-12 weeks.
  • the body weight at the beginning of the experiment was between 38-45g. It was determined that the body weight of the mice was more than 30% higher than that of animals on a normal diet. Random blood sugar and body weight were measured after random testing.
  • mice fed with high-fat diet were randomly divided into model control group ("solvent group"), semaglutide group (administration dose 50nmol/kg), NBB-T007 group (administration dose 50nmol/kg), NBB-T007 -10 group (administration dose: 50 nmol/kg), NBB-T007-12 group (administration dose: 50 nmol/kg).
  • Mice were given the above test substances by subcutaneous injection twice a week, with a dosage volume of 5 mL/kg.
  • the normal model group and the model control group (“solvent group”) were given vehicle control (0.05% NaHCO 3 solution), and were continuously given Medication for 4 weeks. Discontinue the medication, or continue the medication. Test the following indicators:
  • Insulin tolerance ITT test 72 hours after the last dose study, animals were enrolled for ITT study. After the animals were fasted for 1 hour, the 0h blood glucose level was measured. After intraperitoneal injection of 1U/kg insulin injection, the 15min, 30min, and 1h blood glucose were tested. The test results are shown in Figure 37.
  • Glucose tolerance IPGTT test 2 hours after the end of the ITT study, the animals were given the test substance once, and 72 hours later, the animals were enrolled for the IPGTT study. After the animals were fasted overnight for 16 hours, blood was collected from the tail tip to test 0-h fasting blood glucose. Inject a glucose solution with a concentration of 2g/kg intraperitoneally, and at the same time give the test solution by subcutaneous injection, and test the animal's blood sugar at 15min, 30min, 1h, and 2h (the above blood sugar tests all use the second drop of blood). The test results are shown in Figure 38.
  • mice administered the compounds NBB-T007, NBB-T007-10 and NBB-T007-12 prepared in the previous examples had comparable or Better post-meal blood sugar control.
  • Serum biochemistry/serum insulin, C-peptide/blood HbA1C After the ITT study, the animals were euthanized by carbon dioxide, blood was collected from the heart, and heparin sodium anticoagulated whole blood was collected. The blood was divided into two parts, one part was about 120 ⁇ L for testing the HbA1C level, and the other part was used to test the HbA1C level.
  • a portion of 500 ⁇ L whole blood was separated into serum and tested for serum insulin and routine biochemical index tests (total cholesterol CHO, triglyceride TG, high-density lipoprotein HDL, low-density lipoprotein LDL, free fatty acid NEFA, urea UREA, inosine CREA (creatine ), albumin ALB (albumin), total bilirubin TBIL (total bilirubin), alanine aminotransferase ALT, aspartate aminotransferase AST), the test results are shown in Figure 39(a), Figure 39(b) and Figure 39(c).
  • the model control group showed high serum insulin content, a typical diabetes indicator.
  • test mice administered the compounds NBB-T007, NBB-T007-10 and NBB-T007-12 prepared in the previous examples had comparable or better reductions in serum insulin levels trend, and comparable or better protection of liver function, protection of kidney function, and improvement of lipid metabolism.
  • mice administered the compounds NBB-T007, NBB-T007-10 and NBB-T007-12 prepared in the previous examples The test mice had comparable or better postprandial body fat reduction and triglyceride reduction.

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Abstract

L'invention concerne un co-agoniste du récepteur de GLP-1/GIP, une composition pharmaceutique comprenant le composé, son utilisation, et un procédé de traitement et/ou de prévention d'une maladie ou d'un trouble métabolique.
PCT/CN2022/137119 2022-04-29 2022-12-07 Co-agoniste du récepteur de glp-1/gip, composition pharmaceutique le comprenant et son utilisation WO2023207106A1 (fr)

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Citations (5)

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CN101155828A (zh) * 2005-02-11 2008-04-02 安米林药品公司 Gip类似物和具有可选择性质的杂合多肽
CN111825758A (zh) * 2019-04-19 2020-10-27 上海翰森生物医药科技有限公司 Glp-1和gip共激动剂化合物
WO2021113535A1 (fr) * 2019-12-04 2021-06-10 The Scripps Research Institute Conjugués peptidiques et méthodes d'utilisation
CN114222755A (zh) * 2020-05-29 2022-03-22 北京拓界生物医药科技有限公司 Glp-1和gip受体双重激动剂化合物及其应用
CN114349828A (zh) * 2020-11-27 2022-04-15 江苏师范大学 Glp-1/胰高血糖素受体双重激动剂及其应用

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CN101155828A (zh) * 2005-02-11 2008-04-02 安米林药品公司 Gip类似物和具有可选择性质的杂合多肽
CN111825758A (zh) * 2019-04-19 2020-10-27 上海翰森生物医药科技有限公司 Glp-1和gip共激动剂化合物
WO2021113535A1 (fr) * 2019-12-04 2021-06-10 The Scripps Research Institute Conjugués peptidiques et méthodes d'utilisation
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ZHAO FENGHUI, ZHOU QINGTONG, CONG ZHAOTONG, HANG KAINI, ZOU XINYU, ZHANG CHAO, CHEN YAN, DAI ANTAO, LIANG ANYI, MING QIANQIAN, WAN: "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors", NATURE COMMUNICATIONS, vol. 13, no. 1, XP093104614, DOI: 10.1038/s41467-022-28683-0 *

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