WO2024164776A1 - 多肽及其衍生物、组合物及其应用 - Google Patents

多肽及其衍生物、组合物及其应用 Download PDF

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WO2024164776A1
WO2024164776A1 PCT/CN2024/070964 CN2024070964W WO2024164776A1 WO 2024164776 A1 WO2024164776 A1 WO 2024164776A1 CN 2024070964 W CN2024070964 W CN 2024070964W WO 2024164776 A1 WO2024164776 A1 WO 2024164776A1
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Prior art keywords
polypeptide
present application
derivative
pharmaceutically acceptable
acceptable salt
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PCT/CN2024/070964
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English (en)
French (fr)
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潘海
李岩
邹海霞
郝素娟
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杭州先为达生物科技股份有限公司
北京先为达生物科技有限公司
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Publication of WO2024164776A1 publication Critical patent/WO2024164776A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 application relates to the field of polypeptide technology, and in particular to a polypeptide and its derivatives, compositions and applications.
  • Amylin also known as islet amyloid polypeptide (IAPP, amylin or hAMY1-37), is a 37-amino acid polypeptide hormone that belongs to the calcitonin protein family (the family also includes calcitonin (CT), calcitonin gene-related peptide (CGRP), and adrenomedullin (hAM) and its precursors).
  • CT calcitonin
  • CGRP calcitonin gene-related peptide
  • hAM adrenomedullin
  • Amylin is co-secreted with insulin in pancreatic ⁇ cells and is deficient in diabetic patients. It exerts its effects in several different organ systems, mainly through amylin receptors 1-3 (AMYR1-3). Amylin can inhibit glucagon secretion, delay gastric emptying, send satiety signals, and suppress appetite.
  • amylin receptor agonists can be used to treat overweight, obesity, type 1 diabetes, and/or type 2 diabetes.
  • amylin has some disadvantages, such as a high tendency to fibrosis, a short half-life in vivo, and chemical instability at pH 7. Therefore, natural amylin is not suitable for use as a pharmaceutical active ingredient.
  • amylin analogs or derivatives are known in the prior art, which attempt to address some of the known shortcomings of human amylin.
  • a successful example is the amylin analog Pramlintide (trade name Symlin), which has been approved by the FDA for use in type I and type II diabetes.
  • Pramlintide trade name Symlin
  • the half-life of Pramlintide is less than one hour and is used at mealtimes, so patients need to take this drug multiple times a day for treatment.
  • Pramlintide is formulated at pH 4 because it fibrillates at pH 7 and becomes ineffective due to precipitation. Therefore, there is still a need for new amylin analogs or derivatives with increased chemical stability, increased metabolic stability and/or reduced fibrillation tendency.
  • amylin analogs or derivatives that are stable in a wider pH range are needed.
  • new amylin analogs or derivatives that improve efficacy by increasing efficacy, improving efficacy and/or extending half-life are also needed to reduce frequent dosing and improve patient compliance.
  • Pramlintide currently on the market has a half-life of less than one hour, requiring multiple doses of the drug for treatment in one day. It cannot be combined with other drugs in a liquid formulation under neutral conditions.
  • the technical problem to be solved by the present application is to solve the deficiencies in the background technology and to provide a polypeptide and its derivatives, a composition and its application.
  • polypeptide derivative or a pharmaceutically acceptable salt thereof wherein the polypeptide comprises the following amino acid sequence: ASX 3 LS TAX 8 X 9 X 10 RLADF LRHX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILPPT NVGSN TX 37 -NH 2 ;
  • X3 is E, X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X3 is Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X22 is N or R
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X8 is V
  • X3 is E or Q
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X22 is N or R
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X9 is L
  • X3 is E or Q
  • X8 is A or V
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X22 is N or R
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X 9 is T, X 3 is E or Q; X 8 is A or V; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X10 is G, X3 is E or Q; X8 is A or V; X9 is L or T; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X20 is S; X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X20 is T; X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X22 is Q
  • X3 is E or Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X22 is NMeAsn
  • X3 is E or Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X22 is ⁇ MeAsn
  • X3 is E or Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X22 is NMeAsp
  • X3 is E or Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D
  • X37 is P or trans-Hyp.
  • X23 is D; X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X24 is K or R; X25 is P or D; X37 is P or trans-Hyp.
  • X24 is K, X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X25 is P or D; X37 is P or trans-Hyp.
  • X24 is R; X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X25 is P or D; X37 is P or trans-Hyp.
  • X25 is P, X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X37 is P or trans-Hyp.
  • X37 is P, X3 is E or Q; X8 is A or V; X9 is L or T; X10 is G or Q; X19 is S or F; X20 is S or T; X21 is N or D; X22 is N or R; X23 is L or D; X24 is K or R; X25 is P or D.
  • X37 is trans-Hyp
  • X3 is E or Q
  • X8 is A or V
  • X9 is L or T
  • X10 is G or Q
  • X19 is S or F
  • X20 is S or T
  • X21 is N or D
  • X22 is N or R
  • X23 is L or D
  • X24 is K or R
  • X25 is P or D.
  • X3 is Q; preferably, X8, X9, X10 is selected from any of ALG, VLG, VTQ, ATQ, and VLQ; X8 , X9 , X10 is further preferably ATQ; more preferably, X19 is F, X20 is T, X23 is D, X24 is R, X25 is D, and X37 is P; further preferably, X21 is D and/or X22 is R.
  • X3 is Q; preferably, X8, X9, X10 is selected from any of ALG, VLG, VTQ, ATQ, and VLQ; X8 , X9 , X10 is further preferably ATQ; more preferably, X19 is S, X20 is S, X23 is L, X24 is K, X25 is P, and X37 is trans-Hyp; further preferably, X21 is N, Q, E, S, T, A, G, H, K, R or/and X22 is N, Q, E, S, MeAsn, ⁇ MeAsn, or NMeAsp.
  • polypeptide sequence comprises any one of the sequences SEQ ID No.1-SEQ ID No.25.
  • the polypeptide sequence is ASELS TAALG RLADF LRHSS NNLKP ILPPT NVGSNT-trans-Hyp-NH 2 (SEQ ID No. 1).
  • the polypeptide sequence is ASQLS TAVLG RLADF LRHSS NNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 2).
  • the polypeptide sequence is ASELS TAALG RLADF LRHFT DRDRD ILPPT NVGSN TP-NH 2 (SEQ ID No. 3).
  • polypeptide sequence is ASQLS TAVLG RLADF LRHFT DRDRD ILPPT NVGSN TP-NH 2 (SEQ ID No. 4).
  • polypeptide sequence is ASQLS TAATQ
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH 2 (SEQ ID No. 6).
  • the polypeptide sequence is ASQLS TAVTQ RLADFLRHSS NNLKPILPPT NVGSNT-trans-Hyp-NH 2 (SEQ ID No. 7).
  • the polypeptide sequence is ASQLS TAVTQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH 2 (SEQ ID No. 8).
  • the polypeptide sequence is ASQLS TAVLQ RLADFLRHSS NNLKPILPPT NVGSNT-trans-Hyp-NH 2 (SEQ ID No. 9).
  • polypeptide sequence is ASQLS TAVLQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH 2 (SEQ ID No. 10).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS QQLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 11).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS EELKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 12).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS SSLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 13).
  • polypeptide sequence is ASQLS TAATQ RLADF LRHSS N-NMeAsn-LKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 14).
  • polypeptide sequence is ASQLS TAATQ RLADF LRHSS N-NMeAsp-LKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 15).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS QNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 16).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS ENLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 17).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS SNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 18).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS TNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 19).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS ANLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 20).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS GNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 21).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS HNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 22).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS KNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 23).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS RNLKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 24).
  • the polypeptide sequence is ASQLS TAATQ RLADF LRHSS N- ⁇ MeAsn-LKP ILPPT NVGSN T-trans-Hyp-NH 2 (SEQ ID No. 25).
  • the side chain containing fatty acids is in the form of Z1+Z2+Z3, wherein Z1 is a C16-C22 fatty diacid; Z2 is selected from any one of ⁇ Glu, ⁇ Glu, ⁇ Asp, ⁇ Asp, Inp, Trx or Z2 does not exist; Z3 is 0-6 AEEA, for example, it can be 0, 1, 2, 3, 4, 5, 6; and Z1, Z2 and Z3 are connected in sequence by amide bonds.
  • the Z1 is a C22 fatty diacid.
  • the Z1 is a C20 fatty diacid.
  • the Z1 is a C19 fatty diacid.
  • the Z1 is a C18 fatty diacid.
  • the Z1 is a C17 fatty diacid.
  • the Z1 is a C16 fatty diacid.
  • the Z2 is ⁇ Glu.
  • the Z2 is ⁇ Glu.
  • Z2 is ⁇ Asp.
  • the Z2 is ⁇ Asp.
  • Z2 is Inp.
  • Z2 is Trx.
  • Z2 does not exist.
  • Z3 does not exist.
  • the Z3 is 1 AEEA.
  • the Z3 is 2 AEEAs.
  • the Z3 is 3 AEEAs.
  • the Z3 is 4 AEEAs.
  • the Z3 is 5 AEEAs.
  • the Z3 is 6 AEEAs.
  • the polypeptide derivative is M1, or M2, or M3, or M4, or M5, or M6, or M7, or M8, or M9, or M10, or M11, or M12, or M13, or M14, or M15, or M16, or M17, or M18, or M19, or M20, or M21, or M22, or M23, or M24, or M25, or M26, or M27. or M47, or M48, or M49, or M50, or M51, or M52, or M53, or M54, or M55.
  • the present application provides a polypeptide, wherein the polypeptide comprises the above-mentioned polypeptide sequence.
  • polypeptide sequence contained in the polypeptide is any one of SEQ ID No.1-SEQ ID No.25.
  • the present application provides a pharmaceutical composition, which comprises the above-mentioned polypeptide, or the above-mentioned derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises one or more other active pharmaceutical ingredients.
  • the pharmacologically active ingredients include weight regulators, anti-obesity agents, lipid metabolism regulators, blood sugar regulators, hypertension therapeutic agents, cardiovascular regulators, brain system diseases, mental system diseases or nervous system regulators.
  • the pharmacologically active substances are selected from: GLP-1 receptor agonists (including but not limited to GLP-1, GLP-1 analogs, GLP-1 derivatives), GIP receptor agonists (including but not limited to GIP, GIP analogs, GIP derivatives), insulin receptor agonists (including but not limited to insulin, insulin analogs, insulin derivatives).
  • the present application provides a method for preventing and/or treating amylin receptor-related metabolic diseases or fat metabolism disorders, comprising administering to a subject a preventive or therapeutically effective amount of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.
  • the present application provides a method for preventing and/or treating overweight, obesity and/or type I or type II diabetes and/or osteoporosis and/or neuropathic pain, comprising administering to a subject a preventively or therapeutically effective amount of the above-mentioned polypeptide or the above-mentioned derivative or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.
  • the present application provides a method for reducing food intake, comprising administering an effective amount of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition to a subject.
  • the polypeptides and their derivatives or compositions of the present application have significantly improved advantages or positive effects in terms of drug activity, molecular stability, in vivo biological exposure, etc.
  • the polypeptides and their derivatives described in the present application do not contain disulfide bonds compared to traditional amylin analogs or derivatives.
  • the polypeptides and their derivatives described in the present application have unexpectedly high stability, with a downward trend in fibrillation, and still have higher stability even when formulated at neutral or non-acidic pH.
  • the polypeptides or their derivatives of the present application have good pharmacokinetic effects and do not need to be injected as frequently as known amylin derivatives.
  • FIG1 shows the results of thermal acceleration experiments of polypeptide derivative M6 in Example 3.
  • FIG2A shows the results of the weight loss effect of the polypeptide derivatives in Example 4 in the SD rat model over time
  • FIG2B shows the results of the effect of the polypeptide derivatives on food intake in the SD rat model in Example 4 over time
  • Figures 3A and 3C show the results of the weight loss effects of different doses of the polypeptide derivatives in Example 5 in the SD rat model over time;
  • Figures 3B and 3D show the results of the effects of different doses of the polypeptide derivatives on food intake in the SD rat model in Example 5 over time;
  • FIG4A shows the results of the weight loss effects of different doses of the polypeptide derivatives in Example 6 in the DIO SD rat model over time;
  • FIG4B shows the results of the effect of different doses of the polypeptide derivatives on food intake in the DIO SD rat model in Example 6 over time;
  • 5A-5B show the results of the weight loss effect of the polypeptide derivatives in Example 7 in the SD rat model over time
  • Figures 5C-5D show the effect of the polypeptide derivatives in Example 7 on food intake in the SD rat model Impact outcomes over time;
  • FIG. 6 shows a graph showing changes in the concentrations of different molecules in plasma over time in Example 8.
  • polypeptide and peptide and protein are used interchangeably herein and refer to amino acid polymers of any length.
  • the polymer may be linear or branched, it may comprise natural amino acids, and it may be interspersed with non-natural amino acids.
  • derivative refers to a product obtained by modifying the functional groups (such as amino acid residues) of biological macromolecules (such as polypeptides and proteins) by certain compounds or molecules.
  • the modification includes but is not limited to acylation, amidation, esterification, and thioesterification.
  • pharmaceutical composition can refer to the treatment of diseases and can also be used for in vitro culture experiments of cells.
  • pharmaceutical composition usually refers to unit dosage form and can be prepared by any of the methods well known in the pharmaceutical field. All methods include the step of combining the active ingredient with the excipients that constitute one or more auxiliary ingredients. Usually, the composition is prepared by evenly and fully combining the active compound with a liquid excipient, a finely divided solid excipient, or both.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated therewith.
  • the term "pharmaceutically acceptable excipient” may include any solvent, solid excipient, diluent or other liquid excipient, etc., suitable for a specific target dosage form.
  • any conventional excipients incompatible with the compound of the present application such as any adverse biological effect produced or any other component of the pharmaceutically acceptable composition that interacts in a harmful manner, their use is also within the scope of the present application.
  • treatment refers to the use of drugs to obtain a desired pharmacological and/or physiological effect.
  • the results 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 curing a disease and/or adverse effects caused by the disease.
  • treatment covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating symptoms associated with the disease.
  • Treatment covers any administration of a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit a disease in the individual, including but not limited to administering a drug containing a compound described herein to an individual in need.
  • prevent means reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptoms (eg, cancer).
  • amylin receptor-related metabolic diseases are diseases that can improve the symptoms of the subject by regulating the activation of amylin receptors and thus improving their downstream cellular pathways, including hyperlipidemia, atherosclerosis, hypertension, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, obesity, fatty liver, cirrhosis, diseases often associated with diabetes and fat metabolism disorders, such as methods for osteoporosis, methods for treating cognitive disorders, neurodegenerative diseases (such as Parkinson's syndrome, Alzheimer's disease), and treatment of gastrointestinal diseases, such as inflammatory bowel disease, malnutrition, and peptic ulcers.
  • the polypeptide derivative is coupled to the polypeptide via a fatty acid in the form of an amide bond.
  • the fatty acid is a C1 to C25 fatty acid, such as formic acid, acetic acid, C3 fatty acid, C4 fatty acid, C5 fatty acid, C6 fatty acid, C7 fatty acid, C8 fatty acid, C9 fatty acid, C10 fatty acid, C11 fatty acid, C12 fatty acid, C13 fatty acid, C14 fatty acid, C15 fatty acid, C16 fatty acid, C17 fatty acid, C18 fatty acid, C19 fatty acid, C20 fatty acid, C21 fatty acid, C22 fatty acid, C23 fatty acid, C24 fatty acid or C25 fatty acid.
  • C1 to C25 fatty acid such as formic acid, acetic acid, C3 fatty acid, C4 fatty acid, C5 fatty acid, C6 fatty acid, C7 fatty acid, C8 fatty acid, C9 fatty acid, C10 fatty acid, C11 fatty acid, C12 fatty acid, C13 fatty acid, C14
  • the C1-C25 fatty acids include straight-chain fatty acids and branched-chain fatty acids.
  • the C1-C25 fatty acids include saturated fatty acids and unsaturated fatty acids.
  • the fatty acid is caprylic acid, nonanoic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, hexadecanoic acid, hexadecanoic acid, palmitoleic acid, oleic acid, linolenic acid, ricinoleic acid, isocitric acid, eicosapentaenoic acid or docosahexaenoic acid, 1,8-octanedioic acid, 1,7-heptanedicarboxylic acid, 1,10-decanedioic acid, undecanoic acid, dodecanedioic acid, tridecanedioic acid, One or more of
  • the fatty acid part of the present application can be connected to the above polypeptide through a linker.
  • the linker is selected from: - ⁇ Glu-, - ⁇ Glu-, - ⁇ Asp-, - ⁇ Asp-, -Inp-, -Trx-,
  • n is 1, 2 or 3
  • s is any integer from 0 to 6
  • p is any integer from 1 to 8.
  • the term "pharmaceutically acceptable salt” refers to a salt that maintains the biological effectiveness and properties of the derivative of the polypeptide of the present application, and it is usually not undesirable biologically or otherwise.
  • the polypeptide derivative of the present application can form acid and/or base salts through the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphat
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid form of these compounds with a chemically calculated
  • the present invention relates to the preparation of the present invention by reacting a suitable base (e.g., hydroxide, carbonate, bicarbonate, etc., of Na or K) in an amount of stoichiometric amounts, or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. These reactions are usually carried out in water or an organic solvent, or a mixture of the two. Usually, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, where feasible.
  • the present application provides a pharmaceutical composition, which includes the above-mentioned polypeptide or the above-mentioned derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition may further include a buffer system, a preservative, a surface tension agent, a chelating agent, a stabilizer and a surfactant.
  • the buffer is selected from: sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate and tris (hydroxymethyl) aminomethane, N-bis (hydroxyethyl) glycine, tracing, malic acid, lactic acid, succinate, maleic acid, fumaric acid, tartaric acid, aspartic acid or a mixture thereof.
  • Each of these specific buffers or a combination thereof constitutes an alternative of the present application.
  • the medicine or preparation described in the present application is an aqueous medicine or preparation, for example, they can generally be a solution or a suspension.
  • the medicine or preparation is a lyophilized preparation, to which a solvent and/or a diluent are added before use.
  • the present application provides a use of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and/or treating amylin receptor-related metabolic diseases or fat metabolism disorders.
  • the present application provides a use of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating overweight, obesity and/or type I or type II diabetes and/or osteoporosis and/or neuropathic pain.
  • the present application provides a use of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating reduced food intake.
  • the present application provides a use of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof in reducing food intake.
  • the present application also relates to a method for preventing and/or treating amylin receptor-related diseases or dyslipidemia-related diseases, comprising administering to a subject a preventive or therapeutically effective amount of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.
  • the present application provides a method for preventing and/or treating overweight, obesity and/or type I or type II diabetes and/or osteoporosis and/or neuropathic pain, comprising administering to a subject a preventive or therapeutically effective amount of the above-mentioned polypeptide or the above-mentioned derivative or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.
  • the present application provides a method for reducing food intake, comprising administering an effective amount of the above polypeptide or the above derivative or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition to a subject.
  • the method comprises administering the above-mentioned polypeptide or the above-mentioned derivative or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.
  • the polypeptide or the above-mentioned derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is used in combination with other drugs, pharmaceutical compounds or compositions.
  • TBT O-(Benzotriazol-l-yl)-N,N,N,N,-tetramethyluronium Tetrafluoroborate, O-Benzotriazol-N,N,N',N'-tetramethyluronium Tetrafluoroborate
  • TIS Triisopropylsilane, triisopropylsilane
  • Trt Triphenylmethyl, triphenylmethyl
  • NMeAsn N-methylated asparagine
  • polypeptide derivatives prepared in this application are shown in Table 2.
  • Solid phase organic synthesis method Fmoc-protected amino acid strategy, SPPS solid phase synthesis technology were used to complete peptide synthesis, cleavage, oxidation and purification to obtain the target products in Table 2, which were labeled as Cagrilintide, M1-M55 respectively.
  • the peptide derivative resin is washed, transferred out, and dried to a constant weight for cleavage.
  • the above oxidized liquid is filtered with a 0.45 ⁇ m microporous filter membrane; the crude product is purified by using a C-18 column packing preparation column, separated and purified with a suitable gradient at room temperature, and the target product is collected, analyzed, tested, and classified. The purity requirement is ⁇ 90%, and the unqualified target product is collected, separated and purified again with a suitable gradient, and the qualified liquid peak is collected.
  • the above qualified liquid sample is decompressed and freeze-dried to obtain a powdered refined polypeptide derivative freeze-dried powder.
  • polypeptide derivatives prepared in the present application are shown in M1-M55 in Table 2, and the difference lies in different amino acid sequences or different fatty acid side chains.
  • M1-M55 represent derivatives obtained by modifying the amino acid sequence with a fatty acid-containing side chain in the present application, such as the derivatives obtained by modifying SEQ ID No.1-SEQ ID No.10 with the corresponding fatty acid-containing side chains in Table 2.
  • M1 represents the derivative obtained by modifying SEQ ID No.1 with (C20diacid+ ⁇ Glu).
  • the fatty acid-containing side chain is in the form of Z1+Z2+Z3, wherein Z1 is a C16-C22 fatty diacid; Z2 is selected from any one of ⁇ Glu, ⁇ Glu, ⁇ Asp, ⁇ Asp, Inp, Trx or Z2 is absent; Z3 is 0-6 AEEA, for example, 0, 1, 2, 3, 4, 5, 6; Z1, Z2, and Z3 are sequentially connected by amide bonds.
  • the C16-C22 fatty diacid portion is located outside the fatty acid-containing side chain for modification relative to the amino acid sequence, and is at the far end where the side chain is connected to the amino acid sequence.
  • the purpose of this experiment is to use luciferase assay to detect the efficacy of the derivatives of the polypeptide of the present application on human amylin receptor in vitro.
  • CHO-K1/Ga15/AMY3 cells (calcitonin receptor and receptor-activated modified peptide RAMP have been constructed and purchased from GenScript) were transfected with a plasmid containing multiple copies of a cAMP response element (CRE)-driven luciferase expression cassette using standard methods and cultured in F12 medium containing Zeocin 200 ⁇ g/mL, puromycin (2 ⁇ g/mL), hygromycin (100 ⁇ g/mL) and G418 (400 ⁇ g/mL) to obtain a stably transfected amylin receptor/CRE-luc cell line.
  • CRE cAMP response element
  • the lyophilized powder obtained in Example 1 was dissolved in 20 mM phosphate buffer at pH 7.0, and diluted with growth medium (F12 medium containing 10% FBS) to obtain a derivative sample with an initial concentration of 10 nM.
  • the derivative sample was then gradiently diluted with growth medium to obtain seven concentrations of samples with a concentration difference of 5 times from 10 nM to 2 nM-0.4 nM. 50 ⁇ L of sample assay solution of the corresponding concentration was added to each well of a white 96-well plate.
  • CHO cells stably transfected with amylin/CRE-luc were resuspended in growth medium at a certain density, and 50 ⁇ L of the cell resuspension was added to a white 96-well plate with a sample assay solution at a density of about 20,000 cells/well. After incubation at 37°C and 5% CO 2 for 24 hours, 100 ⁇ L of Luciferase substrate was added to each well and incubated for 3 minutes. Finally, the luminescence was measured on SpectraMax L (Molecular Devices) using SoftMax Pro 7.0.3 GxP software, and the standard curve was drawn by the fluorescence value, and the EC50 was calculated. The differences between different peptide derivative groups were statistically calculated by calculating the relative activity (ratio of Cagrilintide to compound EC50), where the relative activity of Cagrilintide was 100%. The results are shown in the following table.
  • Stability test chamber BINDER GmbH
  • 1/100,000 balance Metal-Toledo
  • pH meter Metal-Toledo
  • biological safety cabinet ESCO
  • T2G-II small electric capping machine Changsha Zhongya Pharmaceutical Equipment Co., Ltd.
  • high-speed refrigerated centrifuge Eppendorf
  • sterilization cabinet Xinhua Medical
  • Agilent 1260 high-performance liquid chromatograph Sepax Bio-C18 4.6*250mm 3 ⁇ m Reversed phase chromatography column, TSKgel G2000SWXL 7.8*300mm 3 ⁇ m.
  • the derivative was mixed with sodium dihydrogen phosphate (1.42 mg/mL) at 1 mg/mL, dissolved in ultrapure water, and the pH was adjusted to about 7.4 with hydrochloric acid/sodium hydroxide.
  • the solution was then filtered into a sterilized vial with a 0.22 ⁇ m sterile filter in an ultra-clean workbench.
  • the vial was capped and placed in a 40°C stability test chamber. The tests were performed on the 7th day (7d) and 28th day (28d). During the experiment, the changes in the properties of the polypeptide were observed and recorded.
  • the sample was then centrifuged at 10,000 rpm, 4°C, and 3 min. The supernatant was taken into a liquid phase injection bottle, and the concentration and purity of the polypeptide were detected using the following liquid chromatography method.
  • Reverse phase chromatography conditions flow rate: 1.0 mL/min; autosampler temperature: 15°C; column temperature: 25°C; detection wavelength: 214 nm, mobile phase A: 100% H 2 O + 0.05% TFA, mobile phase B: 100% CAN, elution gradient see the table below:
  • the derivative was mixed with sodium dihydrogen phosphate (1.42 mg/mL) at 1 mg/mL, dissolved in ultrapure water, and the pH was adjusted to about 7.4 with hydrochloric acid/sodium hydroxide.
  • the solution was then filtered into a sterilized vial with a 0.22 ⁇ m sterile filter in an ultra-clean workbench.
  • the vial was capped and placed in a 40°C stability test chamber. The tests were performed at 10 days and 20 days respectively. During the experiment, the changes in the properties of the polypeptide were observed and recorded.
  • the sample was then centrifuged at 10,000 rpm, 4°C, and 3 minutes. The supernatant was taken into a liquid phase injection bottle, and the concentration and purity of the polypeptide were detected using the following liquid chromatography method.
  • SPF male SD rats (7-8 weeks, 200-250g) were used for this experimental study after the quarantine period.
  • the experimental animal breeding conditions were room temperature 20°C ⁇ 23°C, relative humidity 40% ⁇ 50%; during the animal quarantine and the experiment, the feed was Co60 mouse breeding feed 1035, and the drinking water was purified water, supplied with drinking bottles, and water was free.
  • the experimental animals were based on the principle of average weight. There were 5 rats in each derivative test group, and each group of rats was subcutaneously given a 30nmol/kg dose of the derivative or solvent (PBS pH7.4). The dosing time of each group was recorded. After administration, the rats were returned to their living cages, where they could then obtain food and water. Food consumption and rat weight changes were recorded every 24 hours by online or manual recording. The results of the animal experiments are shown in Figures 2A and 2B.
  • SPF male SD rats (7-8 weeks, 220-230g) were used for this experimental study after the quarantine period.
  • the experimental animals were kept at room temperature of 20°C ⁇ 23°C and relative humidity of 40% ⁇ 50%; during the animal quarantine and the experiment, the feed was Co60 mouse breeding feed 1035, and the drinking water was purified water supplied by drinking bottles, and water was available freely.
  • the compounds and doses of each dosing group in the experiment are shown in Table 8.
  • Subcutaneous injection was used for a single dose, and the experiment lasted for 6 days.
  • Day1/Time0 T0
  • Day0 records the initial body weight of the animals and the addition of initial feed
  • Day1-Day5 records the body weight of the experimental animals and the remaining food every day, and calculates the body weight change rate and food intake, and records and reports any abnormal conditions.
  • the rats were in good condition during the experiment, and no abnormal phenomena were observed in the rats.
  • Body weight change (BWTn-BWT 0 )/BWT 0 *100%, BW represents body weight, T 0 and T n represent the time of administration and n hours after administration, respectively.
  • both M41 and M43 reduce the body weight and food intake of animals in a dose-dependent manner; compared with Cagrilintide, M41 and M43 are more effective in reducing the body weight and food intake of animals at the same dose.
  • SPF male DIO SD rats (36-37 weeks, 680-110g, fed with high-fat diet for 34 weeks starting from 3 weeks of age) were used for this experimental study.
  • the experimental animals were kept at room temperature of 20°C to 23°C and relative humidity of 40% to 50%; during the establishment of the animal DIO model and the experiment, the feed was a high-fat diet (D12492), and the drinking water was purified water supplied from a drinking bottle, with free water intake.
  • the first day of administration was recorded as Day1 (D1), where Day0 recorded the initial body weight of the animals and the addition of initial feed, and Day1-Day11 recorded the body weight and remaining food of the experimental animals every day, and calculated the body weight change rate and food intake, and recorded and reported any abnormal conditions.
  • the rats were in good condition during the experiment, and no abnormal phenomena were observed in the rats.
  • Body weight change (BWDn-BWD 1 )/BWD 1 *100%, BW represents body weight, D 1 and Dn represent the first day of administration and the Nth day of administration, respectively.
  • the points in the figure are expressed by the mean ⁇ standard error (standard error of the mean, SEM) method.
  • the cumulative food intake is the total amount of food consumed by each group of animals before a certain time point after administration.
  • the weight loss and food suppression effects of DIO model rats are shown in Figures 4A and 4B.
  • SPF male SD rats (7-8 weeks, 220-230g) were used for this experimental study after the quarantine period.
  • the experimental animals were kept at room temperature of 20°C ⁇ 23°C and relative humidity of 40% ⁇ 50%; during the animal quarantine and the experiment, the feed was Co60 mouse breeding feed 1035, and the drinking water was purified water supplied by drinking bottles, and water was available freely.
  • the single-dose screening experiment was carried out twice in succession.
  • the compounds and doses of each dosing group in the experiment are shown in Table 10. Subcutaneous injection was used for a single dose. The experiment lasted for 6 days.
  • the experimental animals were subcutaneously injected with the corresponding test sample (1mg/kg, 5ml/kg), and the day of administration was recorded as D1.
  • whole blood was collected from animals before administration (-10min) and D1-2h, D1-4h, D1-6h, D2-24h, D3-48h, D4-72h, D5-96h, and D6-120h after administration, and plasma (EDTA anticoagulation) was prepared.
  • the concentration of drug molecules in plasma was detected by liquid chromatography-mass spectrometry (LC-MS/MS), and the drug concentration-time curve was drawn using GraphPad Prism 10, and the pharmacokinetic parameters (Cmax, Tmax, T1/2, AUC, MRT) of the drug were calculated using PKSolver.
  • the changes in the concentrations of different molecules in plasma over time are shown in Figure 6.
  • the experimental results are analyzed and listed in Table 11.

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Abstract

本申请提供了一种多肽，以及所述多肽的衍生物或其药学上可接受的盐，同时，本申请提供了一种药物组合物，该组合物含有本申请所述的多肽或衍生物或其药学上可接受的盐，以及药学上可接受的辅料，上述多肽、多肽的衍生物或其药学上可接受的盐、组合物在疾病预防/治疗领域的应用。

Description

多肽及其衍生物、组合物及其应用 技术领域
本申请涉及多肽技术领域，具体涉及一种多肽及其衍生物、组合物及其应用。
背景技术
胰淀素(amylin)又称胰岛淀粉样多肽(IAPP、胰淀素或hAMY1-37)，是一种37个氨基酸的多肽激素，属于降钙素蛋白家族(该家族还包括降钙素(CT)、降钙素基因相关肽(CGRP)、和肾上腺髓质素(hAM)及其前体)。Amylin在胰岛β细胞中与胰岛素共分泌，在糖尿病人中缺乏。它在几个不同的器官系统中产生作用，主要通过胰淀素受体1-3(AMYR1-3)起作用。amylin可抑制胰高血糖素分泌，延缓胃排空，发出饱足感信号，抑制食欲。临床研究表明，胰淀素受体激动剂可用于治疗超重、肥胖、1型糖尿病和/或2型糖尿病。然而，胰淀素具有一些缺点，如高度的纤维化倾向、短的体内半衰期和pH值为7时的化学不稳定性。因此，天然胰淀素不适合用作药物活性成分。
现有技术中已知大量的胰淀素类似物或衍生物，这些胰淀素类似物或衍生物试图解决人类胰淀素所具有的一些已知缺点。一个成功的例子是胰淀素类似物普兰林肽Pramlintide(商品名Symlin)，它已被FDA批准用于I型和II型糖尿病。但是Pramlintide的半衰期不到一个小时，且在用餐时间使用，因此患者需要在一天内多次服用这种药物进行治疗。并且普兰林肽在pH 4下配制，因为它在pH 7下原纤化，并且由于沉淀而变得无效。因此，仍需要具有增加的化学稳定性、增加的代谢稳定性和/或减少的原纤化倾向的新的胰淀素类似物或衍生物。特别地，需要在更宽的pH范围内稳定的胰淀素类似物或衍生物。此外，还需要通过提高效力、提高疗效和/或延长半衰期来提高效力的新的胰淀素类似物或衍生物，以减少频繁给药和提高患者依从性。目前市场上在售的Pramlintide的半衰期不到一个小时，需要在一天内多次服用这种药物进行治疗。无法在中性条件下与其他药物做在一个液体制剂中。
发明内容
本申请所要解决的技术问题在于解决背景技术中的不足，提供一种多肽及其衍生物、组合物及其应用。
本申请提供了一种多肽的衍生物或其药学上可接受的盐，，所述多肽包含如下氨基酸序列：ASX3LS TAX8X9X10RLADF LRHX19X20X21X22X23X24X25ILPPT NVGSN TX37-NH2；
其中：X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N、Q、E、S、T、A、G、H、K、R或D；X22为N、Q、E、S、NMeAsn、αMeAsn、NMeAsp或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp；所述衍生物包含与所述多肽的N末端连接的含脂肪酸的侧链。
在本申请的一些实施方式中，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X3为E，X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X3为Q，X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X8为A，X3为E或Q；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X8为V，X3为E或Q；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X9为L，X3为E或Q；X8为A或V；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X9为T，X3为E或Q；X8为A或V； X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X10为G，X3为E或Q；X8为A或V；X9为L或T；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X10为Q；X3为E或Q；X8为A或V；X9为L或T；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X19为S，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X19为F；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X20为S；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X20为T；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为N，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为D；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为Q；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为E；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R； X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为S；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为T；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为A；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为G；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为H；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为K；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X21为R；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X22为N或R；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为N，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为R，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为Q，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为E，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为S，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为NMeAsn，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为αMeAsn，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X22为NMeAsp，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X23为L或D；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X23为L，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X23为D；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X24为K或R；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X24为K，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X24为R；X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X25为P或D；X37为P或trans-Hyp。
在本申请的一些实施方式中，X25为P，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X37为P或trans-Hyp。
在本申请的一些实施方式中，X25为D，X3为E或Q；X8为A或V； X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X37为P或trans-Hyp。
在本申请的一些实施方式中，X37为P，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D。
在本申请的一些实施方式中，X37为trans-Hyp，X3为E或Q；X8为A或V；X9为L或T；X10为G或Q；X19为S或F；X20为S或T；X21为N或D；X22为N或R；X23为L或D；X24为K或R；X25为P或D。
在本申请的一些实施方式中，X3为Q；优选地，X8X9X10选自ALG、VLG、VTQ、ATQ、VLQ中任意情况；X8X9X10进一步优选为ATQ；更优选地，X19为F，X20为T，X23为D，X24为R，X25为D，X37为P，进一步优选地，X21为D或/和X22为R。
在本申请的一些实施方式中，X3为Q；优选地，X8X9X10选自ALG、VLG、VTQ、ATQ、VLQ中任意情况；X8X9X10进一步优选为ATQ；更优选地，X19为S，X20为S，X23为L，X24为K，X25为P，X37为trans-Hyp，进一步优选地，X21为N、Q、E、S、T、A、G、H、K、R或/和X22为N、Q、E、S、MeAsn、αMeAsn、NMeAsp。
在本申请的一些实施方式中，所述多肽序列包含SEQ ID No.1-SEQ ID No.25序列中的任一种。
在本申请的一些实施方式中，所述多肽序列为ASELS TAALG RLADF LRHSS NNLKP ILPPT NVGSNT-trans-Hyp-NH2(SEQ ID No.1)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVLG RLADF LRHSS NNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.2)。
在本申请的一些实施方式中，所述多肽序列为ASELS TAALG RLADF LRHFT DRDRD ILPPT NVGSN TP-NH2(SEQ ID No.3)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVLG RLADF LRHFT DRDRD ILPPT NVGSN TP-NH2(SEQ ID No.4)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ
RLADFLRHSS NNLKPILPPT NVGSNT-trans-Hyp-NH2(SEQ ID No.5)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH2(SEQ ID No.6)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVTQ RLADFLRHSS NNLKPILPPT NVGSNT-trans-Hyp-NH2(SEQ ID No.7)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVTQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH2(SEQ ID No.8)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVLQ RLADFLRHSS NNLKPILPPT NVGSNT-trans-Hyp-NH2(SEQ ID No.9)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAVLQ RLADF LRHFT DRDRD ILPPT NVGSN TP-NH2(SEQ ID No.10)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS QQLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.11)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS EELKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.12)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS SSLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.13)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS N-NMeAsn-LKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.14)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS N-NMeAsp-LKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.15)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS QNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.16)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS ENLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.17)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS SNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.18)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS TNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.19)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS ANLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.20)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS GNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.21)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF  LRHSS HNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.22)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS KNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.23)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS RNLKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.24)。
在本申请的一些实施方式中，所述多肽序列为ASQLS TAATQ RLADF LRHSS N-αMeAsn-LKP ILPPT NVGSN T-trans-Hyp-NH2(SEQ ID No.25)。
在本申请的一些实施方式中，所述含有脂肪酸的侧链的形式为Z1+Z2+Z3，其中，Z1为C16-C22脂肪二酸；Z2选自γGlu，αGlu，βAsp，αAsp，Inp，Trx中的任一种或Z2不存在；Z3为0-6个AEEA，例如可以为0、1、2、3、4、5、6个；所述Z1、Z2和Z3之间依次通过酰胺键连接。
在本申请的一些实施方式中，所述Z1为C22脂肪二酸。
在本申请的一些实施方式中，所述Z1为C20脂肪二酸。
在本申请的一些实施方式中，所述Z1为C19脂肪二酸。
在本申请的一些实施方式中，所述Z1为C18脂肪二酸。
在本申请的一些实施方式中，所述Z1为C17脂肪二酸。
在本申请的一些实施方式中，所述Z1为C16脂肪二酸。
在本申请的一些实施方式中，所述Z2为γGlu。
在本申请的一些实施方式中，所述Z2为αGlu。
在本申请的一些实施方式中，所述Z2为βAsp.
在本申请的一些实施方式中，所述Z2为αAsp.
在本申请的一些实施方式中，所述Z2为Inp。
在本申请的一些实施方式中，所述Z2为Trx。
在本申请的一些实施方式中，所述Z2不存在。
在本申请的一些实施方式中，所述Z3不存在。
在本申请的一些实施方式中，所述Z3为1个AEEA。
在本申请的一些实施方式中，所述Z3为2个AEEA。
在本申请的一些实施方式中，所述Z3为3个AEEA。
在本申请的一些实施方式中，所述Z3为4个AEEA。
在本申请的一些实施方式中，所述Z3为5个AEEA。
在本申请的一些实施方式中，所述Z3为6个AEEA。
在本申请的一些实施方式中，所述多肽衍生物是M1，或M2，或M3，或M4，或M5，或M6，或M7，或M8，或M9，或M10，或M11，或M12，或M13，或M14，或M15，或M16，或M17，或M18，或M19，或M20，或M21，或M22，或M23，或M24，或M25，或M26，或M27，或M28，或M29，或M30，或M31，或M32，或M33，或M34，或M35，或M36，或M37，或M38，或M39，或M40，或M41，或M42，或M43，或M44，或M45，或M46，或M47，或M48，或M49，或M50，或M51，或M52，或M53，或M54，或M55。
本申请提供一种多肽，其中，所述多肽包含上述多肽序列。
在本申请的一些实施方式中，所述多肽包含的多肽序列是SEQ ID No.1-SEQ ID No.25中的任一种。
本申请提供一种药物组合物，其包含上述多肽、或上述衍生物或其药学上可接受的盐，以及药学上可接受的辅料。
在本申请的一些实施方式中，所述药物组合物中还包含另一种或多种药物活性成分。所述药理学活性成分包括体重调节剂、抗肥胖剂、脂代谢调节剂、血糖调节剂、高血压治疗剂、心血管调节剂、脑系统疾病、精神系统疾病或神经系统调节剂，优选地，所述药理学活性物质选自：GLP-1受体激动剂(包括但不限于GLP-1、GLP-1类似物、GLP-1衍生物)、GIP受体激动剂(包括但不限于GIP、GIP类似物、GIP衍生物)、胰岛素受体激动剂(包括但不限于胰岛素、胰岛素类似物、胰岛素衍生物)。
上述多肽或上述衍生物或其药学上可接受的盐或组合物在制备预防和/或治疗胰淀素受体相关代谢疾病或脂肪代谢障碍的药物中的用途。
上述多肽或上述衍生物或其药学上可接受的盐或组合物在制备预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的药物中的用途。
上述多肽或上述衍生物或其药学上可接受的盐或组合物在制备预防和/或治疗减少食物摄入的药物中的用途。上述多肽或上述衍生物或其药学上可接受的盐或组合物在减少食物摄入方面的用途。
本申请提供一种预防和/或治疗胰淀素受体相关代谢疾病或脂肪代谢障碍的方法，包括向受试者施用预防或治疗有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述药物组合物。
本申请提供一种预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的方法，包括向受试者施用预防或治疗有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述药物组合物。
本申请提供一种减少食物摄入的方法，包括向受试者施用有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述药物组合物。
与现有技术相比，相同的剂量下，本申请的多肽及其衍生物或组合物在药物活性、分子稳定性、体内生物暴露量等方面具有明显提高的优点或积极效果。同时，本申请所述多肽及其衍生物相比传统胰淀素类似物或衍生物不含二硫键，然而令人意外的是，与传统胰淀素类似物或衍生物相比，本申请所述多肽及其衍生物产生了预料不到的高稳定性，原纤维化呈下降趋势，且即使在中性或非酸性pH下配制时仍具有更高的稳定性。此外，本申请多肽或其衍生物具有良好的药代动力学效果，无需像已知的胰淀素衍生物一样频繁地注射。
附图说明
图1示出了实施例3中多肽衍生物M6的热加速实验结果；
图2A示出了实施例4中多肽衍生物在SD大鼠模型中减重效果随时间变化的结果；
图2B示出了实施例4中多肽衍生物在SD大鼠模型中对食物摄入影响随时间变化的结果；
图3A、3C示出了实施例5中多肽衍生物在SD大鼠模型中不同剂量减重效果随时间变化的结果；
图3B、3D示出了实施例5中多肽衍生物在SD大鼠模型中不同剂量对食物摄入影响随时间变化的结果；
图4A示出了实施例6中多肽衍生物在DIO SD大鼠模型中不同剂量减重效果随时间变化的结果；
图4B示出了实施例6中多肽衍生物在DIO SD大鼠模型中不同剂量对食物摄入影响随时间变化的结果；
图5A-5B示出了实施例7中多肽衍生物在SD大鼠模型中减重效果随时间变化的结果；
图5C-5D示出了实施例7中多肽衍生物在SD大鼠模型中对食物摄入 影响随时间变化的结果；
图6示出了实施例8中不同分子在血浆中的浓度随时间的变化图。
具体实施方式
下面结合实施例进一步说明本申请，应当理解，实施例仅用于进一步说明和阐释本申请，并非用于限制本申请。
除非另外定义，本说明书中有关技术的和科学的术语与本领域内的技术人员所通常理解的意思相同。虽然在实验或实际应用中可以应用与此间所述相似或相同的方法和材料，本文还是在下文中对材料和方法做了描述。在相冲突的情况下，以本说明书包括其中定义为准，另外，材料、方法和例子仅供说明，而不具限制性。以下结合具体实施例对本申请作进一步的说明，但不用来限制本申请的范围。
术语“多肽”和“肽”和“蛋白质”在本文中可互换使用并且是指任何长度的氨基酸聚合物。聚合物可为直链或支链，其可包含天然氨基酸，并且其可间杂有非天然氨基酸。
本文所述“衍生物”是指生物大分子(如多肽、蛋白)的功能基团(如氨基酸残基)被某些化合物或分子修饰后所得到的产物。所述修饰包括但不限于酰基化、酰胺化、酯化、硫酯化。
在本文中，药物组合物可指用于疾病的治疗，也可用于细胞的体外培养实验。用于疾病的治疗时，术语药物组合物通常是指单位剂量形式，并且可以通过制药领域中熟知的方法的任何一种进行制备。所有的方法包括使活性成分与构成一种或多种附属成分的辅料相结合的步骤。通常，通过均匀并充分地使活性化合物与液体辅料、细碎固体辅料或这两者相结合，制备组合物。
在本文中，“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。
在本文中，术语“药学上可接受的辅料”均可包括任何溶剂、固体赋形剂、稀释剂或其他液体赋形剂等等，适合于特有的目标剂型。除了任何常规的辅料与本申请的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本申请所考虑的范围。
在本文中，治疗是指用于指获得期望的药理学和/或生理学效果。所述效 果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病，例如阻滞疾病发展；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述化合物的药物给予有需要的个体。
在本文中，“预防”是指降低疾病、病症、疾患或相关症状(例如癌症)发作(或复发)的可能性。
在本文中，“胰淀素受体相关代谢疾病”是可以通过调节胰淀素受体的激活从而改善其下游细胞通路情况使受试者症状得到改善的疾病，包括高脂血症、动脉粥样硬化、高血压、冠心病、心肌梗塞、脑血栓、脑出血、脑栓塞、肥胖症、脂肪肝、肝硬化，糖尿病和脂肪代谢障碍常伴随的疾病，例如骨质疏松的方法、治疗认知障碍、神经退行性疾病(例如帕金森综合征、阿尔茨海默病)的方法、治疗胃肠道疾病，例如炎性肠病、营养不良、消化道溃疡。
在本申请的一些实施方式中，所述多肽衍生物通过脂肪酸以酰胺键的形式对多肽进行偶联。
在本申请的一些实施方式中，脂肪酸为C1～C25脂肪酸。例如甲酸、乙酸、C3脂肪酸、C4脂肪酸、C5脂肪酸、C6脂肪酸、C7脂肪酸、C8脂肪酸、C9脂肪酸、C10脂肪酸、C11脂肪酸、C12脂肪酸、C13脂肪酸、C14脂肪酸、C15脂肪酸、C16脂肪酸、C17脂肪酸、C18脂肪酸、C19脂肪酸、C20脂肪酸、C21脂肪酸、C22脂肪酸、C23脂肪酸、C24脂肪酸或C25脂肪酸。
本申请中，所述的C1～C25脂肪酸包括直链脂肪酸和支链脂肪酸。
本申请中，所述的C1～C25脂肪酸包括饱和脂肪酸和不饱和脂肪酸。
在本申请的一些实施方式中，所述脂肪酸为辛酸、壬酸、癸酸、十一酸、月桂酸、十三酸、肉豆蔻酸、十五酸、棕榈酸、十七酸、硬脂酸、十九酸、花生酸、二十一酸、二十二酸、二十三酸、二十四酸、棕榈油酸、油酸、亚麻油酸、蓖麻油酸、异柠檬酸、二十碳五烯酸或二十二碳六烯酸、1,8-辛二酸、1,7-庚二甲酸、1,10-癸二酸、十一烷二酸、十二烷二酸、十三烷二酸、 十四烷二酸、十五烷二酸、十六烷二酸、十七烷二酸、十八烷二酸或十九烷二酸、二十烷二酸、二十一烷二酸、二十二烷二酸或二十三烷二酸中的一种或两种以上。
本申请的脂肪酸部分可以通过接头与上述多肽连接。其中，接头有选自：-γGlu-，-αGlu-，-βAsp-，-αAsp-，-Inp-，-Trx-、

的一种或两种以上，其中m是0、1、2或3；n是1、2或3；s是0-6的任意整数；p是1-8的任意整数。
在本申请中，术语“药学上可接受的盐”是指保持了本申请的多肽的衍生物的生物有效性和性质的盐，并且其通常在生物上或在其它方面不是不期望的。在许多情形下，本申请的多肽衍生物通过氨基和/或羧基或与其类似的基团的存在，可形成酸和/或碱盐。
可使用无机酸及有机酸来形成药学上可接受的酸加成盐，例如，乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、chlortheophyllonate、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙磺酸盐、乳酸盐、乳糖酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八烷酸盐、油酸盐、草酸盐、棕榈酸盐、巴莫酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐及三氟乙酸盐。
可由其衍生盐的无机酸包括，例如，盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可由其衍生盐的有机酸包括，例如，乙酸、丙酸、羟乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲烷磺酸、乙烷磺酸、甲苯磺酸、磺基水杨酸等。
可与无机碱及有机碱来形成药学上可接受的碱加成盐。
可由其衍生盐的无机碱包括，例如，铵盐及周期表第I族至第XII族的金属。在某些实施方案中，所述盐衍生自钠、钾、铵、钙、镁、铁、银、锌及铜；尤其适宜的盐包括铵盐、钾盐、钠盐、钙盐及镁盐。
可由其衍生盐的有机碱可包括，例如，伯、仲和叔胺、取代胺包括天然存在的取代胺、环状胺、碱性离子交换树脂等。某些有机胺包括异丙基胺、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪及氨丁三醇。
本申请的药学上可接受的盐可通过惯用化学方法从母体化合物、碱性或酸性部分来合成。通常，这些盐可通过使这些化合物的游离酸形式与化学计 量的适当碱(例如Na或K的氢氧化物、碳酸盐、碳酸氢盐等)进行反应来制备，或通过使这些化合物的游离碱形式与化学计量的适当酸进行反应来制备。这些反应通常是在水或有机溶剂、或二者的混合物中进行。通常，在可行的情况下，使用非水性介质，如醚、乙酸乙酯、乙醇、异丙醇或乙腈是合乎需要的。
本申请提供了一种药物组合物，其包括上述多肽或上述衍生物或其药学上可接受的盐，以及药学上可接受的辅料。在优选实施方案中，所述药物组合物可进一步包含缓冲系统、防腐剂、表面张力剂、螯合剂、稳定剂和表面活性剂。在一些实施方案中，缓冲剂选自：乙酸钠、碳酸钠、柠檬酸盐、甘氨酰甘氨酸、组氨酸、甘氨酸、赖氨酸、精氨酸、磷酸二氢钠、磷酸氢二钠、磷酸钠和三(羟甲基)氨基甲烷、N-二(羟乙基)甘氨酸、曲辛、苹果酸、乳酸、琥珀酸盐、马来酸、延胡索酸、酒石酸、天冬氨酸或其混合物。这些特定缓冲剂中的每一种或其组合构成本申请的备选。在一些实施方案中，本申请所述的药物或制剂是含水药物或制剂，例如，他们通常可以是溶液或悬浮液。在本申请的另一些具体实施方案中，所述药物或制剂是一种冻干制剂，在使用前将溶剂和/或稀释液加入其中。
本申请提供了一种上述多肽或上述衍生物或其药学上可接受的盐在制备预防和/或治疗胰淀素受体相关代谢疾病或脂肪代谢障碍药物中的用途。
本申请提供了一种上述多肽或上述衍生物或其药学上可接受的盐在制备预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的药物中的用途。
本申请提供了一种上述多肽或上述衍生物或其药学上可接受的盐在制备预防和/或治疗减少食物摄入的药物中的用途。
本申请提供了一种上述多肽或上述衍生物或其药学上可接受的盐在减少食物摄入方面的用途。
本申请还涉及预防和/或治胰淀素受体相关疾病或脂肪代谢障碍相关疾病的方法，包括向受试者施用预防或治疗有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述药物组合物。
本申请提供了一种预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的方法，包括向受试者施用预防或治疗有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述药物组合物。
本申请提供了一种减少食物摄入的方法，包括向受试者施用有效量的上述多肽或上述衍生物或其药学上可接受的盐或上述所述的药物组合物。
在本申请的一些实施方式中，包括给药有需要的受试者上述多肽或上述衍生物或其药学上可接受的盐、药物组合物。
在本申请的一些实施方式中，所述多肽或上述衍生物或其药学上可接受的盐、药物组合物与其它药物、药物化合物或组合物联合使用。
缩写
本申请实施例中所用的一些缩写词对应名称或结构形式如下：
AA：Amino Acid，氨基酸
Boc：t-Butyloxy carbonyl，叔丁氧羰基
DCM：dichloromethane，二氯甲烷
DMF：N,N-Dimethyl formamide，二甲基甲酰胺
DIEA：N,N-Diisopropylethylamine，N,N-二异丙基乙胺
EDT：1,2-Ethanedithiol，乙二硫醇
Fmoc：9-fluorenylmethyloxycarbonyl，9-芴基甲氧基羰基
OtBu：叔丁基酯基
Pbf：2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl chloride，2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基
Pip：Piperidine，哌啶
TBT：O-(Benzotriazol-l-yl)-N,N,N,N,-tetramethyluronium Tetrafluoroborate，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯
tBu：tertiary butyl，叔丁基
TFA：Trifluoroacetic acid，三氟乙酸
TIS：Triisopropylsilane，三异丙基硅烷
Trt：Triphenylmethyl，三苯基甲基
αGlu：α谷氨酸
γGlu：γ谷氨酸
αAsp：α天冬氨酸
βAsp：β天冬氨酸
αMeAsn：α甲基化天冬酰胺
NMeAsn：N甲基化天冬酰胺
NMeAsp：N甲基化天冬氨酸
实施例1多肽衍生物的制备
本申请制备的及其多肽衍生物如表2所示。
采用固相有机合成法，利用Fmoc-保护氨基酸策略，SPPS固相合成技术，完成多肽合成，裂解，氧化，纯化即得表2中的目标产物，并依次标记为Cagrilintide、M1-M55。
以化合物Cagrilintide为例，合成过程如下：
1.1固相合成
用Fmoc-Linker MBHA Resin S＝0.32mmol/g，采用Fmoc/tBu工艺，按上述肽序列，以表1方法从C端向N端(从右到左)依次缩合氨基酸连接：
表1多肽合成程序列表
依次偶联下列氨基酸：
A-01Fmoc-Pro-OH,A-02Fmoc-Thr(tBu)-OH,A-03Fmoc-Asn(Trt)-OH,A-04Fmoc-Ser(tBu)-OH,A-05Fmoc-Gly-OH,A-06Fmoc-Val-OH,A-07Fmoc-Asn(Trt)-OH,A-08Fmoc-Thr(tBu)-OH,A-09Fmoc-Pro-OH,A-10Fmoc-Pro-OH,A-1 1Fmoc-Leu-OH,A-12Fmoc-Ile-OH,A-13Fmoc-Pro-OH,A-14Fmoc-Gly-OH,A-15Fmoc-Phe-OH,A-16Fmoc-Asn(Trt)-OH,A-17Fmoc-Asn(Trt)-OH,A-18Fmoc-Ser(tBu)-OH,A-19Fmoc-Ser(tBu)-OH,A-20Fmoc-His(Trt)-OH,A-21Fmoc-Arg(Pbf)-OH,A-22Fmoc-Leu-OH,A-23Fmoc-Phe-OH,A-24Fmoc-Glu(OtBu)-OH,A-25Fmoc-Ala-OH,A-26Fmoc-Leu-OH,A-27Fmoc-Arg(Pbf)-OH,A-28Fmoc-Gln(Trt)-OH,A-29Fmoc-Thr(tBu)-OH,A-30Fmoc-Ala-OH,A-31Fmoc-Cys(Trt)-OH,A-32Fmoc-Thr(tBu)-OH,A-33Fmoc-Ala-OH,A-34Fmoc-Thr(tBu)-OH,A-35Fmoc-Asn(Trt)-OH,A-36Fmoc-Cys(Trt)-OH,A-37Fmoc-Lys(Boc)-OH,A-38Fmoc-Glu-OtBu,A-39C20diacid；
最后形成此多肽衍生物树脂,
将多肽衍生物树脂洗涤转移出干燥至恒重，待裂解。
1.2裂解
裂解试剂的配制：按体积为1g多肽衍生物树脂比10mL±2mL计算裂解试剂用量：TFA:H2O:EDT:TIS＝95:1:2:2依次将所需裂解试剂H2O，TFA，EDT，TIS于裂解反应瓶，裂解试剂温度控制在0～10℃；裂解试剂在搅拌下加入树脂中，待体系温度稳定后；再温控在25～30℃搅拌反应2.5小时。将裂解液滤出，采用5倍液体积量的冰乙醚将其沉淀，滤出沉淀物并采用3倍液体积量的冰乙醚洗涤3次后，室温减压干燥，得固体粗品。
1.3氧化
将粗品研细，准备纯化水，在搅拌下缓慢加入研细粗品，同时滴加乙腈水溶液，待粗品加完并溶解完全后，加入碘甲醇溶液搅拌半小时。
1.4纯化冻干
将上述氧化后液体，用0.45μm的微孔滤膜过滤；粗品纯化采用C-18柱填料制备柱，在常温下用合适梯度进行分离纯化，收集目标产物，分析检测，归类。纯度要求≥90％，将不合格目标物收集，用合适梯度再次对其进行分离纯化，收集合格液体峰。将上述合格的液体样品减压冷冻干燥，得到粉末状精制多肽衍生物冻干粉。
本申请制备的多肽衍生物如表2中M1-M55所示，区别在于氨基酸序列不同或脂肪酸侧链不同。
表2多肽及其衍生物(修饰均在N末端)设计汇总


M1-M55表示本申请用含脂肪酸的侧链修饰氨基酸序列后得到的衍生物，如用表2中的对应含脂肪酸的侧链修饰SEQ ID No.1-SEQ ID No.10后得到的衍生物，例如，M1表示(C20diacid+γGlu)修饰SEQ ID No.1后得到的衍 生物M1。所述含脂肪酸的侧链形式为Z1+Z2+Z3，其中，Z1为C16-C22脂肪二酸；Z2选自γGlu，αGlu，βAsp，αAsp，Inp，Trx中的任一种或Z2不存在；Z3为0-6个AEEA，例如可以为0、1、2、3、4、5、6个；所述Z1、Z2、Z3之间依次通过酰胺键连接。C16-C22脂肪二酸部分相对于氨基酸序列位于用于修饰的含脂肪酸侧链的外侧，处于侧链与氨基酸序列连接的远端。
实施例2衍生物的细胞活性检测
本实验目的在于采用荧光素酶测定法在体外检测本申请多肽的衍生物对人胰淀素受体的效力。
2.1构建胰淀素受体/CRE-luc细胞系
使用标准方法，用含有多拷贝cAMP应答元件(CRE)驱动的荧光素酶表达框的质粒转染CHO-K1/Ga15/AMY3细胞(降钙素受体与受体激活修饰性肽RAMP已构建完成，购自金斯瑞)，在含有吉欧霉素(Zeocin)200μg/mL，嘌呤霉素(2μg/mL)、潮霉素(100μg/mL)和G418(400μg/mL)的F12培养基中培养，以获得具有稳定转染的胰淀素受体/CRE-luc细胞系。
2.2胰淀素荧光素酶测定
将实施例1所得冻干粉用pH7.0的20mM磷酸缓冲液溶解，并用生长培养基(含10％FBS的F12培养基)稀释获得初始浓度10nM的衍生物样品，然后用生长培养基梯度稀释衍生物样品，以获得10nM到2nM-0.4nM之间浓度依次相差5倍的7个浓度的样品，在白色96孔板中每孔中加入相应浓度的样品测定液50μL。
将稳定转染胰淀素/CRE-luc的CHO细胞以一定密度重悬于生长培养基中，在已加入样品测定液的白色96孔板中以约20000个细胞/孔的密度加入50μL细胞重悬液，在37℃和5％CO2条件下孵育24小时后每孔加入Luciferase底物100μL，孵育3分钟，最后在SpectraMax L(Molecular Devices)上以SoftMax Pro 7.0.3 GxP软件测定发光情况，并通过荧光值绘制标准曲线，计算EC50，不同多肽衍生物组间差异通过计算相对活性(Cagrilintide与化合物EC50比值)统计，其中Cagrilintide相对活性为100％。结果如下表所示。
表3胰淀素受体细胞活性结果

实施例3热加速稳定性实验
3.1材料和设备
稳定性试验箱(BINDER GmbH)、十万分之一天平(梅特勒-托利多)、pH计(梅特勒-托利多)、生物安全柜(ESCO)、T2G-Ⅱ小型电动压盖机(长沙中亚制药设备有限公司)、高速冷冻离心机(Eppendorf)、灭菌柜(新华医疗)、Agilent 1260高效液相色谱仪、Sepax Bio-C18 4.6*250mm 3μm反相色谱柱、TSKgel G2000SWXL 7.8*300mm 3μm。
3.2实验方法和结果
将衍生物按1mg/mL与磷酸二氢钠(1.42mg/mL)混合，溶解于超纯水中，用盐酸/氢氧化钠调节pH至7.4左右，之后在超净工作台中用0.22μm无菌滤器过滤溶液至已灭菌西林瓶中。西林瓶压盖后置于40℃稳定性试验箱中。分别于第7天(7d)和28天(28d)进行检测，在实验过程中，观察并记录多肽的性状变化，然后将样品于10000rpm、4℃、3min条件下离心，取上清液至液相进样瓶，并用如下液相色谱方法检测多肽的浓度及纯度。
反相色谱条件流速：1.0mL/min；自动进样器温度：15℃；柱温：25℃；检测波长：214nm，流动相A：100％H2O+0.05％TFA，流动相B：100％CAN，洗脱梯度见下表：
表4液相色谱洗脱梯度列表
结果见下面表5。
表5热加速稳定性的纯度变化

注：变化(7d-0d)＝7d的纯度-0d的纯度，变化(28d-0d)＝28d的纯度-0d的纯度。
其中M6的稳定性数据，具体见图1。从图1中的结果可以看出，M6热加速七天甚至一个月之后，反相的谱图基本上没有变化，加热前后的谱图基本重叠。
将衍生物按1mg/mL与磷酸二氢钠(1.42mg/mL)混合，溶解于超纯水中，用盐酸/氢氧化钠调节pH至7.4左右，之后在超净工作台中用0.22μm无菌滤器过滤溶液至已灭菌西林瓶中。西林瓶压盖后置于40℃稳定性试验箱中。分别于10d和20d进行检测，在实验过程中，观察并记录多肽的性状变化，然后将样品于10000rpm、4℃、3min条件下离心，取上清液至液相进样瓶，并用如下液相色谱方法检测多肽的浓度及纯度。
反相色谱条件
流速：1.0mL/min；自动进样器温度：25℃；柱温：25℃；检测波长：214nm，流动相A：110mM磷酸盐(pH5.8)：ACN＝90：10，流动相B：ACN：IPA：H2O＝85：5：10，洗脱梯度见表6：
表6液相色谱洗脱梯度列表
实验结果如表7所示。
表7

热稳定性实验结果显示，相比于对照Cagriliintide分子组，本申请所述多肽分子均体现出了明显更优的稳定性。
实施例4动物实验
采用SPF级雄性SD大鼠(7-8周，200-250g)，经检疫期后用于本实验研究。实验动物饲养条件室温20℃～23℃，相对湿度40％～50％；动物检疫期间和实验过程中，饲料采用Co60鼠繁殖饲料1035，饮水为纯化水，用饮水瓶供应，自由摄水。实验动物按体重平均原则，各衍生物测试组5只大鼠，经皮下给予各组大鼠30nmol/kg剂量的衍生物或溶媒(PBS pH7.4)。记录每组的给药时间。给药后，将大鼠放回它们的居住笼，然后在其中它们可以获取食物和水。通过在线记录或手动记录，每24小时记录食物消耗和大鼠体重变化。动物实验结果如图2A和2B所示。
具体的实验结果见图2A和2B，与Cagrilintide相比，本申请的候选分子活性要显著高于Cagrilintide，其中M6是活性最高的分子，明显高于Cagrilintide。
实施例5 SD大鼠的药效实验-剂量依赖性研究
采用SPF级雄性SD大鼠(7-8周，220-230g)，经检疫期后用于本实验研究。实验动物饲养条件室温20℃～23℃，相对湿度40％～50％；动物检疫期间和实验过程中，饲料采用Co60鼠繁殖饲料1035，饮水为纯化水，用饮水瓶供应，自由摄水。实验动物按体重平均原则分10组(记为A1-A10)，n＝5，分别为溶媒(Vehicle)组、Cagrilintide(高、中、低)剂量组、M41(高、中、低)剂量组和M43(高、中、低)剂量组。实验各给药组化合物及剂量如表8所示。采用皮下注射方式，单次给药，实验共6天，给药当天 记为Day1/Time0(T0)。其中Day0记录动物初始体重及添加初始饲料，Day1-Day5每天记录实验动物体重及剩余食物，并计算体重变化率及食物摄入量，同时记录并汇报任何异常情况。大鼠在实验过程中状态均良好，未观察到大鼠异常现象。体重变化＝(BWTn-BWT0)/BWT0*100％，BW代表体重值，T0和Tn分别代表给药时和给药后n小时。图中各点采用平均值±标准误差(standard error of the mean,SEM)方法表示。累积摄食量是给药后在某个时间点之前每个动物摄入的总食物量。分子的量效关系如图3A-3D所示。
表8剂量依赖性研究实验供试品活性成分和给药剂量
从图3A-3D的结果可以看出，M41和M43都剂量依赖性地降低动物体重和摄食量；与Cagrilintide相比，同等剂量下M41和M43降低动物体重和摄食量效果更好。
实施例6 DIO SD大鼠的药效实验-剂量依赖性研究
采用SPF级雄性DIO SD大鼠(36-37周，680-110g，从3周龄开始用高脂饲料饲养34周)，用于本实验研究。实验动物饲养条件室温20℃～23℃，相对湿度40％～50％；动物DIO模型构建期间和实验过程中，饲料采用高脂饲料(D12492)，饮水为纯化水，用饮水瓶供应，自由摄水。实验动物按体重平均分6组(n＝5)，分别命名为B1-B6，实验各组给药化合物活性成分 及剂量如表9所示。采用皮下注射方式，每天给药1次，连续给药10天。给药第一天记为Day1(D1)，其中Day0记录动物初始体重及添加初始饲料，Day1-Day11每天记录实验动物体重及剩余食物，并计算体重变化率及食物摄入量，同时记录并汇报任何异常情况。大鼠在实验过程中状态均良好，未观察到大鼠异常现象。体重变化＝(BWDn-BWD1)/BWD1*100％，BW代表体重值，D1和Dn分别代表给药第一天和给药第N天。图中各点采用平均值±标准误差(standard error of the mean,SEM)方法表示。累积摄食量是给药后在某个时间点之前每组动物摄入的总食物量。DIO模型大鼠体重降低及食物抑制效果如图4A、4B所示。
表9 DIO SD大鼠的药效实验-剂量依赖性研究实验供试品活性成分和给药剂量
从图4A、4B中的结果可以看出，在DIO模型大鼠上M41和M43都剂量依赖性地降低动物体重和摄食量；与Cagrilintide相比，同等剂量下M41和M43降低动物体重和摄食量效果更好。
实施例7 SD大鼠的药效实验-单一剂量筛选
采用SPF级雄性SD大鼠(7-8周，220-230g)，经检疫期后用于本实验研究。实验动物饲养条件室温20℃～23℃，相对湿度40％～50％；动物检疫期间和实验过程中，饲料采用Co60鼠繁殖饲料1035，饮水为纯化水，用饮水瓶供应，自由摄水。单一剂量筛选实验分先后两次开展，两次实验动物分别按体重平均分组原则分组(n＝5)，分别命名为C1-C6，D1-D9。实验各给药组化合物及剂量如表10所示。采用皮下注射方式，单次给药，实验共6天，给药当天记为Day1/Time0(T0)，Day1-Day5每天记录实验动物体重及剩 余食物，并计算相对体重变化率及食物摄入量，同时记录并汇报任何异常情况。大鼠在实验过程中状态均良好，未观察到大鼠异常现象。体重变化＝(BWTn-BWT0)/BWT0*100％，BW代表体重值，T0和Tn分别代表给药和给药后n小时。图中各点采用平均值±标准误差(standard error of the mean,SEM)方法表示。不同分子的药效比较如图5A-5D所示。
表10单一剂量筛选实验供试品活性成分和给药剂量
从图5A-5D的结果可以看出，与Cagrilintide相比，本申请的多肽及其衍生物的药效均与Cagrilintide相当或有所提升。
实施例8在SD大鼠中的药代动力学研究
SPF级实验动物(雄性，6-8周，200-240g)检验检疫合格后，按体重平均分为3组(n＝3)，分别为M41组，M43组和Cagrilintide组。实验动物经皮下注射相对应供试品(1mg/kg，5ml/kg)，给药当天记为D1。给药D1收集动物给药前(-10min)及给药后D1-2h，D1-4h，D1-6h，D2-24h，D3-48h，D4-72h，D5-96h，D6-120h全血并制备血浆(EDTA抗凝)。利用液质联用(LC-MS/MS)方法对血浆中药物分子的浓度进行检测，利用GraphPad Prism 10绘制药物浓度-时间曲线，并用PKSolver对药物的药代动力学参数(Cmax、Tmax、T1/2、AUC、MRT)进行计算。不同分子在血浆中的浓度随时间的变化如图6所示。实验结果分析列于表11中。
表11不同分子的比对结果汇总

从图6以及表11中的数据可以看出，相比于Cagrilintide，多肽分子M41与M43显示出了明显更高的生物暴露量。
虽然本案已以实施例揭露如上然其并非用以限定本案，任何所属技术领域中具有通常知识者，在不脱离本案的精神和范围内，当可作些许的更动与润饰，故本案的保护范围当视后附的专利申请范围所界定者为准。

Claims (12)

  1. 一种多肽衍生物或其药学上可接受的盐，所述多肽包含如下氨基酸序列：ASX3LS TAX8X9X10RLADF LRHX19X20X21X22X23X24X25ILPPT NVGSN TX37-NH2
    其中：
    X3为E或Q；
    X8为A或V；
    X9为L或T；
    X10为G或Q；
    X19为S或F；
    X20为S或T；
    X21为N、Q、E、S、T、A、G、H、K、R或D；
    X22为N、Q、E、S、NMeAsn、αMeAsn、NMeAsp或R；
    X23为L或D；
    X24为K或R；
    X25为P或D；
    X37为P或trans-Hyp；
    所述衍生物包含与所述多肽的N末端连接的含脂肪酸的侧链。
  2. 根据权利要求1所述的衍生物或其药学上可接受的盐，其中，
    X3为Q；
    优选地，X8X9X10选自ALG、VLG、VTQ、ATQ、VLQ中任意情况；X8X9X10进一步优选为ATQ；
    更优选地，
    X19为F，X20为T，X23为D，X24为R，X25为D，X37为P；进一步优选地，X21为D或/和X22为R；
    或X19为S，X20为S，X23为L，X24为K，X25为P，X37为trans-Hyp，进一步优选地，X21为N、Q、E、S、T、A、G、H、K、R或/和X22为N、Q、E、S、NMeAsn、αMeAsn、NMeAsp。
  3. 根据权利要求1或2所述的衍生物或其药学上可接受的盐，其中，所述多肽序列包含SEQ ID No.1至SEQ ID No.25序列中的任一种。
  4. 根据权利要求1-3任一项所述的衍生物或其药学上可接受的盐，
    所述含有脂肪酸的侧链的形式为Z1+Z2+Z3，
    其中，Z1为C16-C22脂肪二酸；
    Z2选自γGlu，αGlu，βAsp，αAsp，Inp，Trx中的任一种或Z2不存在；
    Z3为0-6个AEEA，例如可以为0、1、2、3、4、5、6个；
    所述Z1、Z2和Z3之间依次通过酰胺键连接。
  5. 根据权利要求4所述的衍生物或其药学上可接受的盐，所述多肽衍生物选自M1至M55。
  6. 一种多肽，其中，所述多肽包含权利要求1-5任一项所涉及的多肽序列。
  7. 一种药物组合物，其包括权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽，以及药学上可接受的辅料。
  8. 权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽在制备预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的药物中的用途。
  9. 权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽在减少食物摄入方面的用途。
  10. 一种预防和/或治疗超重、肥胖症和/或I型或II型糖尿病和/或骨质疏松症和/或神经性疼痛的方法，包括向受试者施用预防或治疗有效量的权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽或权利要求7所述的药物组合物。
  11. 一种减少食物摄入的方法，包括向受试者施用预防或治疗有效量的权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽或权利要求7所述的药物组合物。
  12. 一种预防和/或治疗胰淀素受体相关疾病或脂肪代谢障碍的方法，包括向受试者施用预防或治疗有效量的权利要求1-5任一项所述的衍生物及其药学上可接受的盐或权利要求6所述的多肽或权利要求7所述的药物组合物。
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