WO2022007805A1 - 新型多肽及其治疗用途 - Google Patents

新型多肽及其治疗用途 Download PDF

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Publication number
WO2022007805A1
WO2022007805A1 PCT/CN2021/104805 CN2021104805W WO2022007805A1 WO 2022007805 A1 WO2022007805 A1 WO 2022007805A1 CN 2021104805 W CN2021104805 W CN 2021104805W WO 2022007805 A1 WO2022007805 A1 WO 2022007805A1
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Prior art keywords
compound
formula
peptide
preceding aspects
group
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PCT/CN2021/104805
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English (en)
French (fr)
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韩捷
沈志超
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鸿绪生物医药科技（北京）有限公司
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Priority to CA3185229A priority Critical patent/CA3185229A1/en
Priority to US18/015,029 priority patent/US20230263896A1/en
Priority to EP21836893.4A priority patent/EP4177263A1/en
Priority to AU2021304762A priority patent/AU2021304762B2/en
Priority to CN202180048716.7A priority patent/CN116113429A/zh
Publication of WO2022007805A1 publication Critical patent/WO2022007805A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a polypeptide compound and its use in medicine.
  • Metabolic syndrome is a combination of medical conditions that increase the risk of developing type 2 diabetes, atherosclerotic vascular disease, heart disease, and stroke.
  • the medical parameters that define metabolic syndrome include diabetes mellitus, impaired glucose tolerance, elevated fasting blood glucose, insulin resistance, central obesity, hypertension, elevated total cholesterol and triglycerides, elevated LDL cholesterol, and decreased HDL cholesterol.
  • Diabetes includes type 1 diabetes, type 2 diabetes, and gestational diabetes. According to the World Health Organization (WHO), the prevalence of diabetes in developed countries is 5% to 10%. By 2030, the number of diabetic patients in the world will double from 2000. More than 50% of people with undiagnosed diabetes worldwide are prediabetic, and there are even more people with prediabetes than with diabetes.
  • WHO World Health Organization
  • the number of people with diabetes in China has reached 114 million, and another 500 million people have low glucose tolerance and impaired glucose regulation, and are about to become diabetics. More than half of patients do not know they have the disease.
  • the great harm of diabetes mainly lies in serious complications and high mortality. Data show that diabetes is the leading cause of lower extremity amputation and new blindness in adults.
  • Obesity is a medical condition in which excess fat accumulation in the body can adversely affect health and life expectancy, and due to its increasing prevalence among adults and children, it has become one of the modern preventable causes of death. It increases the likelihood of various other diseases, including heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis, and is often caused by excess food intake, reduced energy A combination of consumption and genetic susceptibility.
  • Asians have higher levels of visceral fat than Caucasians for the same body mass index (BMI), so Asians are more insulin resistant than Caucasians, and Asians with normal weight type 2 diabetes are more likely than non-diabetics The patient's insulin sensitivity decreased significantly.
  • GLP-1 receptor agonists can control blood sugar by promoting insulin secretion, improving insulin sensitivity, and reducing glucagon release. Therefore, GLP-1 drugs are suitable for the treatment of metabolic diseases, especially diabetes.
  • GLP-1 receptor agonists exenatide, liraglutide, etc. have all shown the effect of reducing body weight in animal tests and clinical trials, with relatively few side effects. Liraglutide is already approved in the U.S. for diabetes and obesity, making it the only drug available for both conditions.
  • GLP-1 drugs all have the side effects of large gastrointestinal reactions. These side effects affect the patient's medication compliance and reduce the drug usage and user base. According to the physiological mechanism of GLP-1 receptors, GLP-1 drugs have a slow effect on weight loss, and the clinical treatment of obesity requires a higher dose than that of diabetes treatment, resulting in more prominent side effects of gastrointestinal reactions. Most patients lost an average of no more than 5% of their body weight, and their weight rebounded significantly after drug withdrawal.
  • the polypeptide compound of the present invention can not only reduce blood sugar, but also can significantly reduce triglyceride and total cholesterol, especially low density cholesterol (LDL), and is expected to solve the two problems of high blood sugar and high blood lipid in the "three highs" at the same time. cardiovascular health benefits.
  • the polypeptides of the present invention are more suitable for diabetic patients or pre-diabetic populations than statins.
  • the polypeptides of the present invention may provide new options for the treatment of these diseases.
  • the polypeptide of the present invention is suitable for various diseases caused by abnormal lipid metabolism, including hyperlipidemia, non-alcoholic fatty liver and the like.
  • the polypeptides of the present invention can also be used for diseases such as hypertension, arteriosclerosis, coronary heart disease, peripheral arterial disease, stroke, or any combination of these diseases.
  • the polypeptide of the present invention is not only beneficial to enhance the curative effect, reduce the toxic and side effects, but also facilitate the patient, thereby improving the therapeutic effect.
  • the polypeptides of the present invention can also be used for diabetes treatment like GLP-1 drugs. Since these polypeptides reduce body weight and body fat and improve insulin resistance, they not only have excellent hypoglycemic effects, but also have special effects on a high proportion of diabetic patients who are ill due to overweight. Although many overweight or obese people in the population are not medically classified as diabetics, they have pre-diabetic symptoms such as glucose intolerance and excessive postprandial blood glucose. The polypeptide of the present invention is also suitable for pre-diabetic people.
  • the present invention relates to a peptide compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,
  • X1 represents an amino acid residue selected from L, K, C or Y, or formula (II), or formula (III);
  • X2 represents an amino acid residue selected from Q, A, aib or Y;
  • X3 represents an amino acid residue selected from An amino acid residue of E, C or K, or formula (II), or formula (III);
  • X4 represents an amino acid residue selected from E, C or K, or formula (II), or formula (III);
  • X5 represents An amino acid residue selected from V or A,
  • X6 represents an amino acid residue selected from K, R, C or Q, or formula (II), or formula (III);
  • X7 represents an amino acid residue selected from I or V;
  • X8 represents an amino acid residue selected from E, Q, N, K, C, or A, or formula (II), or formula (III);
  • X9 represents an amino acid residue selected from I, L, C, or K, or formula (II), or formula (III);
  • X10 represents
  • n1 is an integer from 1 to 7
  • the amino acid residue of formula (II) containing a side chain amino group is modified by a long-acting group at its side chain amino group
  • the amino acid residue of formula (III) containing a side chain sulfhydryl group is modified by a long-acting group at its side chain sulfhydryl group.
  • modification preferably, formula (II) is a lysine residue, formula (III) is a cysteine residue
  • one or two amino acids selected from the group consisting of S or a side chain containing an amino group or a sulfhydryl group are added, and the carboxyl group of the C-terminal amino acid is optionally amidated to a C-terminal amide containing a side chain amino group
  • the amino acid residue of the sulfhydryl group has the structure shown in formula (II) or formula (III); when formula (II) or formula (III) is a C-terminal amino acid, its carboxyl moiety is COOH or CONH 2 , preferably, formula ( II) is lysine and formula (III) is cysteine;
  • the long-acting group has the structure of formula (IV):
  • O1 represents the structure of formula (V) or (VI):
  • n2 is an integer of 6-24, preferably 10-24, more preferably 16-22;
  • O2 to O8 is independently composed of the following amino acid residues or Any of the long chain structures represents: ⁇ -Glu, ⁇ -Glu, ⁇ -Asp, ⁇ -Asp, ⁇ -hGlu, ⁇ -hGlu, Gly, Ala, ⁇ -Ala, GABA or PEG2, or in O2 to O8 One or more of are absent, provided that at least two of O2 to O8 are present, preferably, O2 to O8 contain at least one negatively charged moiety.
  • O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of ⁇ Glu-PEG2- ⁇ Glu-, ⁇ Glu-PEG2-2 ⁇ Glu-, ⁇ Glu -PEG2-, ⁇ Glu-2 ⁇ PEG2-, ⁇ Glu-3 ⁇ PEG2-, ⁇ Glu-PEG2- ⁇ Glu-PEG2-, ⁇ Glu-2 ⁇ PEG2- ⁇ Glu-, ⁇ Glu-2 ⁇ PEG2-2 ⁇ Glu-, 2 ⁇ Glu -, 2 ⁇ Glu-PEG2-, 2 ⁇ Glu-PEG2- ⁇ Glu-, 2 ⁇ Glu-PEG2- ⁇ Glu-, 2 ⁇ Glu-2 ⁇ PEG2-, 2 ⁇ Glu-2 ⁇ PEG2- ⁇ Glu-, 2 ⁇ Glu-2 ⁇ PEG2-2 ⁇ Glu-.
  • O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of ⁇ Glu-PEG2-, ⁇ Glu-2 ⁇ PEG2-, ⁇ Glu- 3xPEG2-, O1 represents the structure of formula (V) or (VI).
  • O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of ⁇ Glu-PEG2-, ⁇ Glu-2 ⁇ PEG2-, ⁇ Glu- 3xPEG2-, O1 represents the structure of formula (V).
  • O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of ⁇ Glu-2 ⁇ PEG2-, ⁇ Glu-3 ⁇ PEG2-, O1 represents the structure of formula (V).
  • O2-O3-O4-O5-O6-O7-O8- represents the linker ⁇ Glu-2 ⁇ PEG2- and O1 represents the structure of formula (V).
  • O2-O3-O4-O5-O6-O7-O8- represents the linker ⁇ Glu-2 ⁇ PEG2-
  • O1 represents the structure of formula (V), wherein n2 is Integer from 16-22.
  • the lysine side chain amino group is conjugated with a long-acting group
  • the molecular structure is abbreviated as K(x18) in this application, and has the structure of formula (VII):
  • the lysine side chain is conjugated to a long-acting group
  • the molecular structure is abbreviated as K(x20) in this application, and has the structure of formula (VIII):
  • the amino acid containing a side chain sulfhydryl group added at the C-terminal of X10 is modified at its side chain sulfhydryl group by the long-acting group of formula (IV), optionally, the side chain sulfhydryl group and the long-acting group of the C-terminal amino acid are A reactive group that can react with a sulfhydryl group to form a covalent bond can be added as required.
  • connection relationship between the side chain sulfhydryl group of the side chain sulfhydryl group-containing amino acid and the long-acting group is: the side chain sulfhydryl group of the side chain sulfhydryl group-containing amino acid-sulfhydryl reactive group-optional linking group L-long-acting group.
  • the side-chain sulfhydryl group of the side-chain sulfhydryl-containing amino acid is reacted with a Michael-reactive acceptor (eg, maleimide or vinyl sulfone) or a thiol-reactive group (eg, iodoacetic acid or bromoacetic acid) ) is connected with one end of the connecting group L after the reaction, preferably, the other end of the connecting group L is further connected with the long-acting group of formula IV to form a covalent bond.
  • a Michael-reactive acceptor eg, maleimide or vinyl sulfone
  • a thiol-reactive group eg, iodoacetic acid or bromoacetic acid
  • the linking group L is a long chain formed by -(CH 2 ) n3 - and -(CH 2 CH 2 O) n4 - arranged and combined according to structural requirements, and linked together by covalent bonds; or One or both ends of -(CH 2 ) n3 -, -(CH 2 CH 2 O) n4 - optionally contain amino or carboxyl groups, which are linked together by amide bonds to form a long chain, for example, the linking group L Selected from -NH-(CH 2 ) n5 -(CH 2 CH 2 O) n6 -(CH 2 ) n7 -, -NH-(CH 2 ) n5 -(CH 2 CH 2 O) n6 -(CH 2 ) n7 -NH-, -NH-(CH 2 ) n5 -(CH 2 CH 2 O) n6 -(CH 2 ) n7 -CO-, -NH-(CH 2 ) n5
  • L is -NH-CH 2 - (CH 2 CH 2 O) 3 - (CH 2) 3 -NH-.
  • non-limiting illustrative examples of Michael reaction acceptors or thiol reactive groups attached to the linking group L include
  • the wavy line is the point of attachment to the long-acting group of formula (IV), eg, to O8. * is the point of attachment of the side chain sulfhydryl group of the amino acid containing the side chain sulfhydryl group to other parts of the amino acid.
  • any amino acid in the polypeptide fragment represented by X10 can be substituted with an amino acid whose side chain contains an amino group or a sulfhydryl group, and the amino acid has the structure of formula (II) or formula (III).
  • the amino acid containing a side chain amino group is modified by a long-acting group in its side chain amino group, preferably, the long-acting group has the structure of formula (IV);
  • the amino acid containing a side chain sulfhydryl group is in Its side chain sulfhydryl group is modified by a long-acting group, preferably, the long-acting group has the structure of formula (IV), optionally, between the side chain sulfhydryl group and the long-acting group can be added as required, which can react with the sulfhydryl group.
  • a reactive group that forms a covalent bond is optionally, between the side chain sulfhydryl group and the long-acting group can be added as required, which can react
  • the cysteine side chain sulfhydryl group is conjugated to a long-acting group
  • the molecular structure is abbreviated as C(x18) in this application, and has the structure of formula (IX):
  • the cysteine side chain sulfhydryl group is conjugated to a long-acting group
  • the molecular structure is abbreviated as C(x20) in this application, and has the structure of formula (X):
  • polypeptide fragments GPPSGAPPP, GPSSGKPPP, GPSSGEPPP, GPSSaibAPPP represented by X10 can be reduced by 1, 2, 3, 4, 5, 6, 7, 8 amino acids from the C-terminus of the fragment to the N-terminus of the fragment.
  • X1 is L.
  • X1 is Y.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is K.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is C.
  • X2 is Q.
  • X2 is Y.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X2 is A.
  • X2 is Aib.
  • X3 is E.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X3 is K.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X3 is C.
  • X4 is E.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X4 is K.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X4 is C.
  • X5 is V.
  • X5 is A.
  • X6 is K.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X6 is R.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X6 is Q.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X6 is C.
  • X7 is I.
  • X7 is V.
  • X8 is E.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X8 is N.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X8 is Q.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X8 is A.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X8 is K.
  • X8 is C.
  • X9 is I.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X9 is K.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X9 is Aib.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X9 is V.
  • X10 is absent.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPPPSK.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPPPSC.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPPPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPPPC.
  • X10 is GPSSGAPPP.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAPP.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGAP.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSGA.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSSG.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPSS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is GP.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X10 is G.
  • X1 is L and X10 is GPSSGAPPPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSGAPPPC.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSGAPPP.
  • X1 is L and X10 is GPSSGAPP.
  • a peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSGAP.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSGA.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSSG.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPSS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L and X10 is GP.
  • X2 is Q and X10 is GPSSGAPPPS.
  • X2 is Q and X10 is GPSSGAPPPK.
  • X2 is Q and X10 is GPSSGAPPPC.
  • X2 is A and X10 is GPSSGAPPPS.
  • X2 is A and X10 is GPSSGAPPPK.
  • X2 is A and X10 is GPSSGAPPPC.
  • X2 is aib and X10 is GPSSGAPPPS.
  • X2 is aib and X10 is GPSSGAPPPK.
  • X2 is aib and X10 is GPSSGAPPPC.
  • X2 is Q and X10 is GPSSGAPPP.
  • X2 is Q and X10 is GPSSGAPP.
  • X2 is Q and X10 is GPSSGAP.
  • X2 is Q and X10 is GPSSGA.
  • X2 is Q and X10 is GPSSG.
  • X2 is Q and X10 is GPSS.
  • X2 is Q and X10 is GPS.
  • X2 is Q and X10 is GP.
  • X2 is Q and X10 is G.
  • X2 is A and X10 is GPSSGAPPP.
  • X2 is A and X10 is GPSSGAPP.
  • X2 is A and X10 is GPSSGAP.
  • X2 is A and X10 is GPSSGA.
  • X2 is A and X10 is GPSSG.
  • X2 is A and X10 is GPSS.
  • X2 is A and X10 is GPS.
  • X2 is A and X10 is GP.
  • X2 is A and X10 is G.
  • X2 is A and X9 is K.
  • X2 is aib and X10 is GPSSGAPPP.
  • X2 is aib and X10 is GPSSGAPP.
  • X2 is aib and X10 is GPSSGAP.
  • X2 is aib and X10 is GPSSGA.
  • X2 is aib and X10 is GPSSG.
  • X2 is aib and X10 is GPSS.
  • X2 is aib and X10 is GPS.
  • X2 is aib and X10 is GP.
  • X2 is aib and X10 is G.
  • X2 is aib and X9 is K.
  • X2 is Y and X10 is G.
  • X1 is L and X2 is Q.
  • X1 is L and X2 is A.
  • X1 is L and X2 is aib.
  • X1 is L, X2 is Q, and X10 is GPSSGAPPPS.
  • X1 is L, X2 is Q, and X10 is GPSSGAPPPK.
  • X1 is L, X2 is Q, and X10 is GPSSGAPPPC.
  • X1 is L, X2 is Q, and X10 is GPSSGAPPP.
  • X1 is L, X2 is Q, and X10 is GPSSGAPP.
  • X1 is L, X2 is Q, and X10 is GPSSGAP.
  • X1 is L, X2 is Q, and X10 is GPSSGA.
  • X1 is L, X2 is Q, and X10 is GPSSG.
  • X1 is L, X2 is Q, and X10 is GPSS.
  • X1 is L, X2 is Q, and X10 is GPS.
  • X1 is L, X2 is Q, and X10 is GP.
  • X1 is L, X2 is Q, and X10 is G.
  • X1 is L, X2 is A, and X10 is GPSSGAPPPS.
  • X1 is L, X2 is A, and X10 is GPSSGAPPPK.
  • X1 is L, X2 is A, and X10 is GPSSGAPPPC.
  • X1 is L, X2 is A, and X10 is GPSSGAPPP.
  • X1 is L, X2 is A, and X10 is GPSSGAPP.
  • X1 is L, X2 is A, and X10 is GPSSGAP.
  • X1 is L, X2 is A, and X10 is GPSSGA.
  • X1 is L, X2 is A, and X10 is GPSSG.
  • X1 is L, X2 is A, and X10 is GPSS.
  • X1 is L, X2 is A, and X10 is GPS.
  • X1 is L, X2 is A, and X10 is GP.
  • X1 is L, X2 is A, and X10 is G.
  • X1 is L, X2 is aib, and X10 is GPSSGAPPPS.
  • X1 is L, X2 is aib, and X10 is GPSSGAPPPK.
  • X1 is L, X2 is aib, and X10 is GPSSGAPPPC.
  • X1 is L, X2 is aib, and X10 is GPSSGAPPP.
  • X1 is L, X2 is aib, and X10 is GPSSGAPP.
  • X1 is L, X2 is aib, and X10 is GPSSGAP.
  • X1 is L, X2 is aib, and X10 is GPSSGA.
  • X1 is L, X2 is aib, and X10 is GPSSG.
  • X1 is L, X2 is aib, and X10 is GPSS.
  • X1 is L, X2 is aib, and X10 is GPS.
  • X1 is L, X2 is aib, and X10 is GP.
  • X1 is L, X2 is aib, and X10 is G.
  • X1 is L
  • X2 is A
  • X9 is K
  • X1 is L
  • X2 is aib
  • X9 is K
  • X1 is L
  • X2 is Y
  • X9 is K
  • X1 is L
  • X2 is Q
  • X5 is V
  • X10 is GPSSGAPPPS
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is Q, X5 is V, and X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is Q, X5 is V, and X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X5 is V
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X10 is GPSSGAPPPC.
  • X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPS.
  • X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPK.
  • X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPK
  • X1 is L
  • X2 is A
  • X3 K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X10 is GPSSGAPPPC.
  • X2 is A and X5 is V.
  • X2 is aib and X5 is V.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is A, and X5 is V.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is aib, and X5 is V.
  • X1 is L, X2 is aib, and X5 is V.
  • X1 is L, X2 is A, X3 is K, and X5 is V.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, and X5 is V.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I.
  • X2 is Q and X9 is L.
  • X2 is Q, X9 is L, and X10 is GPSSGAPPPS.
  • X2 is Q, X9 is L, and X10 is GPSSGAPPPK.
  • X2 is Q, X9 is L, and X10 is GPSSGAPPPC.
  • X2 is A and X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPS.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPC.
  • X2 is aib and X9 is L.
  • X2 is aib, X9 is L, and X10 is GPSSGAPPPS.
  • X2 is aib, X9 is L, and X10 is GPSSGAPPPK.
  • X2 is aib, X9 is L, and X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X9 is L
  • X10 is GPSSGAPPPS.
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is Q, X9 is L, and X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is Q, X9 is L, and X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X9 is L
  • X10 is GPSSGAPPPS.
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is A, X9 is L, and X10 is GPSSGAPPPK.
  • the peptide compound according to any of the preceding aspects in some embodiments, X1 is L, X2 is A, X9 is L, and X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is Q
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is Q
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is Q
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is A
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X9 is L
  • X10 is GPSSGAPPPS.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPK.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is V
  • X9 is L
  • X10 is GPSSGAPPPC.
  • X1 is Y and X2 is Q.
  • X1 is Y, X3 is K, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, X8 is N, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, X8 is N, and X9 is L.
  • X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, X8 is N, and X9 is I.
  • X1 is Y
  • X2 is Y
  • X3 is K
  • X5 is V
  • X7 is I
  • X8 is E
  • X9 is L.
  • X1 is L and X9 is I.
  • X1 is L and X9 is L.
  • X1 is L, X2 is Q, and X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, and X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, and X9 is L.
  • X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.
  • X1 is L and X2 is A.
  • X1 is L, X2 is A, and X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is A, X5 is V, and X9 is L.
  • the peptide compound according to any of the preceding aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X9 is L.
  • X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.
  • X1 is L and X2 is aib.
  • X1 is L
  • X2 is aib
  • X9 is L.
  • X1 is L
  • X2 is aib
  • X5 is V
  • X9 is L.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X9 is L.
  • X1 is L
  • X2 is aib
  • X3 is K
  • X5 is V
  • X7 is I
  • X8 is E
  • X9 is L.
  • X1 is L, X4 is E, X9 is I or L, X11 is I, X12 is L, and X14 is A.
  • X1 is L, X4 is E, X5 is V, X9 is I or L, X11 is I, X12 is L, and X14 is A.
  • X1 is L, X3 is K, X4 is E, X5 is V, X9 is I or L, X11 is I, X12 is L, and X14 is A.
  • X1 is L
  • X2 is A or aib
  • X3 is K
  • X4 is E
  • X5 is V
  • X9 is I or L
  • X11 is I
  • X12 is L
  • X14 is A.
  • X1 is L
  • X2 is A or aib
  • X3 is K
  • X4 is E
  • X5 is V
  • X7 is I
  • X9 is I or L
  • X11 is I
  • X1 is L
  • X2 is A or aib
  • X3 is K
  • X4 is E
  • X5 is V
  • X6 is R
  • X7 is I
  • X9 is I or L
  • X11 is I
  • X12 is L
  • X13 is L
  • X14 is A.
  • X1 is L
  • X2 is A or aib
  • X3 is K
  • X4 is E
  • X5 is V
  • X6 is R
  • X7 is I
  • X8 is E
  • X9 is I or L
  • X11 is I
  • X12 is L
  • X13 is L
  • X14 is A.
  • X1 is L
  • X3 is K
  • X4 is E
  • X5 is V
  • X6 is R
  • X7 is I
  • X8 is E
  • X9 is I or L
  • X11 is I
  • X12 is L
  • X13 is L
  • X14 is A.
  • X1 is L
  • X2 is A or aib
  • X3 is K
  • X4 is E
  • X5 is V
  • X6 is R
  • X7 is I
  • X8 is E
  • X9 is I or L
  • X11 is I
  • X12 is L
  • X13 is L
  • X14 is A
  • X10 is selected from GPSSGAPPP, GPPSGAPPP, GPSSGKPPP, GPSSGEPPP, GPSSaibAPPP, GPSSGAPP, GPSSGAP, GPSSGA, GPSSG, GPSS, GPS, GP, or G , or at the C-terminus of X10 add one or two amino acids selected from the group consisting of S or a side chain containing an amino group or a sulfhydryl group, and the carboxyl group of the C-terminal amino acid is optionally amidated to a C-terminal amide, the amino acid containing an amino group or a
  • X1 is L and X2 is Y.
  • X1 is L
  • X2 is Y
  • X5 is V.
  • X1 is L
  • X2 is Y
  • X3 is K
  • X5 is V.
  • X1 is L
  • X2 is A, aib or Y
  • X4 is E
  • X11 is I or S.
  • X1 is L
  • X2 is A, aib or Y
  • X4 is E
  • X11 is I.
  • X1 is L
  • X2 is A, aib or Y
  • X3 is K
  • X4 is E
  • X11 is I.
  • X2 is Q
  • X9 is K
  • the sequence consisting of X10 and the C-terminal amino acid is not GPSSGAPPPS or GPSSGAPPPSK.
  • At least one of X1, X3, X4, X6, X8, X9, X11, X12, X14 is of formula (II) or formula (III).
  • the peptide compound according to any of the preceding aspects in some embodiments, at least one of X1, X3, X4, X6, X8, X9, X11, X12, X14 is of formula (II) or formula (III), and at least one of The side chain of formula (II) or formula (III) is conjugated to a long-acting group or a modifying group.
  • at least one of X1, X4, X8, X11, X12, X14 is of formula (II) or formula (III).
  • At least one of X1, X3, X4, X6, X8, X9, X11, X12, X14 is of formula (II) or formula (III), and X10,
  • the sequence consisting of C-terminal X10 and C-terminal amino acids does not contain formula (II) or formula (III).
  • At least one of X1, X3, X4, X6, X8, X9, X11, X12, X14 is of formula (II) or formula (III), and X10 and The sequence consisting of C-terminal X10 and C-terminal amino acids is not GPSSGAPPPK, GPSSGAPPPC, GPSSGAPPPSC or GPSSGAPPPSK.
  • X2 represents an amino acid residue selected from A, aib, or Y
  • X12 is formula (II) or formula (III).
  • X1 is formula (II) or formula (III).
  • X1 is K(x18).
  • X1 is K(x20).
  • X3 is formula (II) or formula (III).
  • X3 is K(x18).
  • X3 is K(x20).
  • X4 is formula (II) or formula (III).
  • X4 is K(x18).
  • X4 is K(x20).
  • X6 is formula (II) or formula (III).
  • X6 is K(x18).
  • X6 is K(x20).
  • X8 is formula (II) or formula (III).
  • X8 is K(x18).
  • X8 is K(x20).
  • X9 is formula (II) or formula (III).
  • X9 is K(x18).
  • X9 is K(x20).
  • X11 is of formula (II) or formula (III).
  • X11 is K(x18).
  • X11 is K(x20).
  • X12 is formula (II) or formula (III).
  • X12 is K(x18).
  • X12 is K(x20).
  • X14 is formula (II) or formula (III).
  • X14 is K(x18).
  • X14 is K(x20).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned peptide compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention relates to methods of treating or preventing the following diseases or conditions: impaired glucose tolerance (IGT), hyperglycemia, type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome and neurodegenerative diseases, in particular For delaying or preventing disease progression in type 2 diabetes, delaying progression from impaired glucose tolerance to type 2 diabetes; delaying progression from type 2 diabetes to insulin-requiring diabetes; treating metabolic syndrome, for regulating appetite, inducing Satiety, reducing food intake, increasing energy expenditure, treating obesity or preventing overweight; preventing weight regain after successful weight loss; treating a disease or condition associated with overweight or obesity; treating bulimia; treating binge eating; treating lipids Abnormalities, atherosclerosis, hypertension, coronary heart disease, ⁇ -blocker poisoning; non-alcoholic fatty liver disease (NAFLD, non-alcoholic fatty liver disease) (can be divided into simple fatty liver (SFL), non-alcoholic fatty liver disease steatohepatitis (NASH) and its associated cirrhosis); for suppressing motility of the gastrointestinal disorders
  • the present invention relates to the use of a peptide compound of any of the preceding aspects, or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof, in the manufacture of a medicament for lowering blood sugar or treating diabetes.
  • the invention relates to the use of a peptide compound of any of the preceding aspects, or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof, for the manufacture of a medicament for weight loss.
  • the present invention relates to the use of a peptide compound of any of the preceding aspects, or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof, in the manufacture of a medicament for lowering blood lipids. It is preferred to lower blood lipid components selected from the group consisting of cholesterol, triglycerides, free fatty acids, low density lipoprotein cholesterol.
  • the invention relates to a method for the preparation of a peptide compound according to any of the preceding aspects, wherein the method of preparation is by chemical synthesis.
  • the present inventors carried out a series of structural modifications to the GLP-1 receptor agonist peptide derivatives, including the selection of specific amino acids, or the introduction of new amino acids at the C-terminal of the peptide, or the substitution of the C-terminal amino acid residues of the peptide.
  • the unique long-acting group is linked to the polypeptide through the side chain sulfhydryl group of the cysteine residue or the side chain amino group of the lysine residue at the C-terminal of the polypeptide to obtain a new class of peptide compounds.
  • Figure 1 Compounds 12 and 15 of the present invention reduce blood glucose in db/db mice.
  • Figure 2 Compounds of the invention 55, 58 and 243 reduce body weight in DIO mice.
  • Amino acid refers to a molecule that contains both amino and carboxyl functional groups, the amino and carboxyl groups of an alpha-amino acid being attached to the same carbon atom (alpha carbon). The alpha carbon may additionally have 1-2 organic substituents.
  • Amino acids contain L and D isomers and racemic mixtures. Unless otherwise specified, the amino acid residues in the polypeptide sequence of the present invention are all L isomers, namely L-amino acids, and D-amino acids are represented by adding a lowercase letter "d" before the amino acid name or abbreviation, such as dK.
  • amino acid sequences of the present invention contain conventional one-letter or three-letter codes for naturally occurring amino acids, as well as generally recognized three-letter codes for other amino acids, such as Tic(1,2,3,4-tetrahydroisoquinoline -3-carboxylic acid), Aib ( ⁇ -aminoisobutyric acid) or GABA ( ⁇ -aminobutyric acid).
  • Abbreviated codes for common molecular structures include:
  • hGlu is homoglutamic acid
  • ⁇ -hGlu is the L isomer of -HNCH(CO-)CH 2 CH 2 CH 2 COOH;
  • ⁇ -hGlu is the L isomer of -HNCH(COOH)CH 2 CH 2 CH 2 CO-;
  • ⁇ -Glu is the L isomer of -HNCH(CO-)CH 2 CH 2 COOH;
  • ⁇ -Glu or gGlu is the L isomer of -HNCH(COOH)CH 2 CH 2 CO-;
  • ⁇ -Asp is the L isomer of -HNCH(CO-)CH 2 COOH;
  • ⁇ -Asp is the L isomer of -HNCH(COOH)CH 2 CO-;
  • ⁇ -Ala is -HN-CH 2 -CH 2 -COOH
  • PEG2 is 2-(2-(2-aminoethoxy)ethoxy)acetic acid (CAS No. 134978-97-5).
  • amino acid composition of the polypeptides of the present invention can be altered without substantially affecting its biological activity.
  • a polypeptide sequence can contain one or more conservative amino acid substitutions.
  • Conservative amino acid substitutions are the replacement of one amino acid residue by another amino acid residue with a similar side chain.
  • Amino acid residues are classified in the literature according to the properties of their side chains.
  • Amino acid residues containing basic side chains include lysine, arginine, histidine; amino acid residues containing acidic side chains and their amide side chains include aspartic acid, glutamic acid, asparagine, glutamine ; small aliphatic, non-polar or weakly polar side chain amino acid residues include glycine, alanine, threonine, serine, proline; large aliphatic, non-polar side chain amino acid residues include leucine , isoleucine, valine; aromatic amino acid residues include phenylalanine, tryptophan, tyrosine; sulfur-containing side chain amino acid residues include cysteine, methionine.
  • the derivative comprises a substituent comprising a lipophilic moiety and optionally 1-3 negatively charged moieties, wherein one of the negatively charged moieties is distal to the lipophilic moiety .
  • the substituent is attached to the side chain of the amino acid at the C-terminus of the sequence. If the C-terminus of the sequence is lysine, it is attached to the epsilon amino group of the lysine residue.
  • an "expression vector” includes a vector capable of expressing DNA operably linked to regulatory sequences, such as promoter regions, capable of affecting the expression of such DNA fragments. Such additional fragments may include promoter and terminator sequences, and optionally, one or more origins of replication, one or more selectable markers, enhancers, polyadenylation signals, and the like. Expression vectors are typically derived from plasmid or viral DNA, or may contain elements of both. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, phage, recombinant virus, or other vector, which, when introduced into an appropriate host cell, results in the expression of cloned DNA.
  • Appropriate expression vectors are well known to those skilled in the art and include those that are replicable in eukaryotic and/or prokaryotic cells as well as those that remain episomal or that integrate into the host cell genome.
  • the invention further provides a nucleic acid (which may be DNA or RNA) encoding the compound, a vector comprising such a nucleic acid, and a nucleic acid comprising such a nucleic acid or The host cell for the expression vector.
  • treating includes inhibiting, slowing, stopping or reversing the progression or severity of an existing symptom or condition.
  • treatment includes prevention, treatment and/or cure.
  • Prevention refers to preventing an underlying disease and/or preventing the worsening of symptoms or the development of a disease.
  • therapeutic effect refers to an effect resulting from treatment of an individual that alters, generally ameliorates or ameliorates the symptoms of a disease or condition, or cures the disease or condition.
  • a “therapeutically effective amount” or “therapeutically effective dose” refers to an amount of a substance, compound, material, or composition comprising a compound that is at least sufficient to produce a therapeutic effect after administration to a subject. Thus, it is an amount necessary to prevent, cure, ameliorate, retard or partially retard the symptoms of a disease or disorder.
  • a prophylactically effective amount or “prophylactically effective dose” refers to an amount of a substance, compound, material or composition comprising a compound that, when administered to a subject, will have the desired prophylactic effect, eg, prevent or delay a disease or symptom occurrence or recurrence, and reduce the likelihood of occurrence or recurrence of disease or symptoms.
  • a fully prophylactically effective dose need not occur by administering one dose, and may occur only after administering a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations.
  • the term "patient” refers to a mammal, such as a human.
  • Certain compounds of the present invention are generally effective over a wide dosage range. For example, a dose administered once a week may range from about 0.05 to about 30 mg per person per week. Certain compounds of the present invention may be administered daily. Additionally, certain compounds of the present invention may be administered once a week.
  • the therapeutic agents according to the described embodiments will be administered with suitable pharmaceutically acceptable carriers, excipients, and other agents that are incorporated into the formulation to provide improved transfer, delivery, tolerability, and the like.
  • suitable pharmaceutically acceptable carriers, excipients, and other agents that are incorporated into the formulation to provide improved transfer, delivery, tolerability, and the like.
  • suitable formulations can be found in the pharmacopoeia known to all medicinal chemists: Remington's Pharmaceutical Sciences (15th edition, Mack Publishing Company, Easton, Pa. (1975)), especially chapter 87 of Blaug, Seymour therein.
  • Such formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing (cationic or anionic) carriers (eg, LipofectinTM), DNA conjugates, anhydrous slurries, oil-in-water and Water-in-oil emulsions, emulsion polyethylene glycols (polyethylene glycols of various molecular weights), semisolid gels, and semisolid mixtures containing polyethylene glycols. Any of the foregoing mixtures may be suitable for use in treatment or therapy according to the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and that the formulation is physiologically compatible and tolerated by the route of administration.
  • the term "pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration .
  • Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard bibliography in the field, which is incorporated herein by reference.
  • Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.
  • Liposomes and non-aqueous vehicles, such as fixed oils, can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • Formulations to be used for clinical in vivo administration must be sterile. This can be easily achieved by filtration through sterile membranes.
  • the compounds of the present invention can react with any of a variety of inorganic or organic acids to form pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable salts and common methods of preparing them are well known in the art. See, eg, Handbook of Pharmaceutical Salts: Properties, Selection and Use. Second Revised Edition (Wiley-VCH, 2011); SM Berge et al. "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, 1977 1 moon.
  • Commonly used pharmaceutically acceptable salts include trifluoroacetate, phosphate, acetate, citrate, hydrochloride and the like.
  • the compounds of the present invention can react with any of various inorganic or organic bases to form pharmaceutically acceptable salts, and commonly used pharmaceutically acceptable salts include sodium salts, potassium salts, ammonium salts and the like.
  • compositions of the embodiments are formulated to be compatible with their intended route of administration.
  • routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (ie, topical), transmucosal, and rectal.
  • Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: sterile injectable diluents such as water, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol, methylparaben, phenol or m-cresol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as ethyl acetate salts, citrates or phosphates, and agents to adjust osmotic pressure, such as sodium chloride or dextrose.
  • sterile injectable diluents such as water, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents
  • Antibacterial agents such as benzyl alcohol, methylparaben, phenol or m-cresol
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be packaged in ampoules, vials, disposable syringes, multiple dose vials made of glass or plastic, or injection pens.
  • injection pens There are two main types of injection pens, one is a one-time pre-filled pen, which contains medicines, no need to replace the medicine refill, and can be thrown away after use; the other is a more commonly used durable injection pen. It is composed of an injection pen and a drug refill, and the refill can be replaced after use.
  • compositions suitable for injectable use include sterile aqueous solutions (herein water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and fluid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coatings such as lecithin to maintain the desired particle size in the case of dispersions, and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, m-cresol, ascorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars, polyols (such as mannitol, sorbitol), sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the compounds of this invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating a compound of the present invention into a sterile vehicle that contains a dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation are vacuum drying and freeze-drying to obtain a powder containing the active ingredient and any additional desired ingredient from a sterile-filtered solution of those previously enumerated. .
  • the compounds are delivered as an aerosol spray from a pressurized container or dispenser containing a gas of a suitable propellant, such as carbon dioxide, or a nebulizer.
  • a gas of a suitable propellant such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the permeation barrier are used in the formulation.
  • penetrants are generally known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • one or more of the compounds of the present invention may be formulated into an ointment, ointment, gel, or cream as generally known in the art.
  • the compounds can also be prepared for rectal delivery in the form of suppositories (eg, with conventional suppository bases such as cocoa butter or other glycerides) or retention enemas.
  • suppositories eg, with conventional suppository bases such as cocoa butter or other glycerides
  • retention enemas e.g., retention enemas.
  • the compounds of the present invention may be prepared with carriers that will protect them against rapid elimination from the body, such as sustained/controlled release formulations, including implants and microencapsulated delivery systems.
  • sustained/controlled release formulations including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.
  • these active ingredients can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in macroemulsions.
  • colloidal drug delivery systems eg, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules
  • hydroxymethylcellulose or gelatin microcapsules hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in macroemulsions.
  • Sustained release formulations can be prepared.
  • suitable sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention in the form of shaped articles such as films or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (eg, poly(2-hydroxyethyl-methylpropionate), or poly(vinyl alcohol)), polylactides (US Pat. No.
  • Polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the research hotspots in recent years.
  • albumin microspheres chitosan microspheres, gelatin microspheres, etc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in US Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier one or more of said compounds of the invention.
  • the specifications for the dosage unit forms of the embodiments are indicated by and are directly dependent on the unique characteristics of the compounds of the present invention and the particular therapeutic effect to be achieved, and the limitations inherent in the art of formulation of such compounds of the present invention for the treatment of individuals sex.
  • the pharmaceutical composition can be placed in a container, pack, or dispenser with instructions for administration.
  • the present invention provides a method for treating type 2 diabetes in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating type 2 diabetes in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the administration is subcutaneous.
  • the present invention also provides a method of treating type 2 diabetes in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and concurrently, separately, or sequentially administering the effective amount of one or more other active ingredients.
  • the other active ingredient(s) are currently available glucose-lowering drugs from drugs that are considered standard of care prior to administration (such as those from the American Diabetes Association). industry guidelines).
  • the present invention also provides methods of treating or preventing the following diseases or conditions: impaired glucose tolerance (IGT), hyperglycemia, type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome and neurodegenerative diseases, particularly with For delaying or preventing disease progression in type 2 diabetes, delaying progression from impaired glucose tolerance to type 2 diabetes; delaying progression from type 2 diabetes to insulin-requiring diabetes; treating metabolic syndrome, for regulating appetite, inducing satiety Foot sensation, reduce food intake, increase energy expenditure, treat obesity or prevent overweight; prevent weight regain after successful weight loss; treat diseases or conditions associated with overweight or obesity; treat bulimia; treat binge eating; treat dyslipidemia , atherosclerosis, hypertension, coronary heart disease, ⁇ -blocker poisoning; non-alcoholic fatty liver disease (NAFLD, non-alcoholic fatty liver disease) (can be divided into simple fatty liver (SFL), non-alcoholic fatty liver disease Steatohepatitis (NASH) and its associated cirrhosis); for the inhibition of motility of the gastrointestinal tract, for use in conjunction
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Ataxia Disorders (eg, spinocerebellar ataxia), Kennedy disease, myotonic dystrophy, Lewy body dementia, multi-systemic atrophy, amyotrophic lateral cord Sclerosis, primary lateral sclerosis, spinal muscular atrophy, prion-related diseases (eg Creutzfeldt-Jacob disease), multiple sclerosis, telangiectasia, Batten disease , corticobasal degeneration, subacute combined degeneration of the spinal cord, tuberculosis, Tay-Sachs disease, toxic encephalopathy, infantile Refsum disease, Refsum disease Symm's disease, neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Joseph disease, Sandhoff disease ), Shy-Drager syndrome, wobbly hedgehog syndrome, proteopathy, cerebral neurodegenerative diseases, especially neurodegenerative diseases such as Alzheimer'
  • Aloc or AOC allyloxycarbonyl: allyloxycarbonyl; Bom, benzyloxymethyl: benzyloxymethyl; 2-Br-Z, 2-bromobenzyloxycarbonyl: 2-bromobenzyloxycarbonyl; tBu, t-butyl: tert-butyl; Bz, benzoyl : benzoyl; Bzl, benzyl: benzyl; Boc, tert-butoxycarbonyl: tert-butoxycarbonyl; CHO, formyl: formyl; cHx, cyclohexyl: cyclohexyl; Cbz or Z, benzyloxycarbonyl: benzyloxycarbonyl; 2-Cl -Z,2-chlorobenzyloxycarbonyl:2-chlorobenzyloxycarbonyl; Fm,9-fluorenylmethyl:9-fluorenylmethyl; Fmoc,9-fluor
  • ACN acetonitrile: acetonitrile
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate: benzotriazole-1-tris(trimethylamino)-hexafluorophosphate (Carter condensate);
  • DCC N,N'-Dicyclohexylcarbodiimide : dicyclohexylcarbodiimide; DCM: dichloromethane;
  • DEPBT 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one:3-(diethoxyphosphoryloxy) -1,2,3-Benzotriazin-4-one;
  • DIC N,N'-Diisopropylcarbodiimide: N,N'-diisopropylcarbodiimide
  • DIPEA or DIEA
  • diisopropylethylamine diisopropyl
  • Linear peptides were synthesized using Boc solid-phase peptide synthesis or Fmoc solid-phase peptide synthesis. If Fmoc is used to chemically synthesize a polypeptide whose C-terminus is a carboxyl group, Wang resin is usually used; the polypeptide whose C-terminus is an amide usually uses Rink amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin and other similar resins). If Boc chemistry is used to synthesize a polypeptide whose C-terminus is a carboxyl group, Pam resin is usually used; for a polypeptide whose C-terminus is an amide, MBHA resin is usually used.
  • condensing agents and activators are DIC and HOBT, other optional peptide bond condensing agents include EDC, BOP, HBTU, DEPBT, TBTU, etc.
  • EDC EDC
  • BOP BOP
  • HBTU HBTU
  • DEPBT TBTU
  • Peptides can be synthesized manually or using a peptide solid-phase synthesizer.
  • the Fmoc protecting group was removed with 20% piperidine/DMF.
  • the Boc protecting group was removed with TFA.
  • the peptide bond condensation reaction was monitored with Ninhydrin (2,2-Dihydroxyindane-1,3-dione) reagent.
  • resins preloaded with C-terminal amino acids can be used, or resins without amino acids can be used.
  • the method of loading the first amino acid on Rink Amide resin can refer to the common practice in the industry.
  • a common method is briefly described as follows: Weigh an appropriate amount of resin, remove the Fmoc protecting group with 20% piperidine/DMF in a solid phase synthesis tube (15 mL/g resin, 30 min ⁇ 2), and wash the resin with DMF. Weigh the Fmoc amino acid, HATU, HOAT and 10 times the equivalent of NMM equivalent to 5 times the resin amino group, add DMF and mix well, and then transfer to the solid phase synthesis tube. After reacting overnight, the resin was washed with DMF. 1:1 acetic anhydride/pyridine (v/v) was added to the solid phase synthesis tube, evacuated after 30 minutes, and the resin was washed with DMF. The first amino acid is loaded.
  • Properly protected structural units are used in the synthesis process, such as the above standard amino acids, Fmoc-8-amino-3,6-dioxa-octanoic acid (CAS No. 166108-71-0), Fmoc-Glu-OtBu (CAS No. 84793-07-7).
  • Introduction of fatty acid moieties can be accomplished using building blocks such as, but not limited to, mono-tert-butyl eicosanedioate.
  • the unreacted peptide intermediate can be capped with acetic anhydride (10 equiv) and excess collidine (20 equiv).
  • the commonly used cleavage reagent is TFA.
  • Boc-Cys(4-MeBzl)-OH Boc-Asp(OcHx)-OH, Boc-Glu(OcHx)-OH, Boc-His(Bom)-OH, Boc-Lys(2-Cl-Z)-OH , Boc-Asn(Xan)-OH, Boc-Arg(Tos)-OH, Boc-Ser(Bzl)-OH, Boc-Thr(Bzl)-OH, Boc-Trp(CHO)-OH and Boc-Tyr( 2-Br-Z)-OH
  • the side chain amino group of lysine can be protected with allyloxycarbonyl (aloc) or Fmoc protection. If the side chain carboxyl group of aspartic acid or glutamic acid is used for lactam synthesis or acylation reaction, the carboxyl group should be converted to allyl ester or 9-fluorenyl methyl protection, such as Boc-Glu(OAllyl)-OH, Boc -Glu(Ofm)-OH.
  • HF is usually used to cut, add 5 ml of HF per 0.1 mmol of resin, and add reagents such as p-cresol, p-mercaptophenol or anisole at the same time, and the mixture is cooled in an ice bath. under stirring for 1 hour. After vacuum drying HF, the polypeptide was precipitated with ice ether, and the precipitate was collected by centrifugation, separated and purified by HPLC, and freeze-dried to obtain the final product.
  • reagents such as p-cresol, p-mercaptophenol or anisole
  • Crude peptides were dissolved in a suitable mixture of water and acetonitrile (e.g. water/acetonitrile (3:1)) and purified by reverse phase preparative HPLC (e.g. AKTA purifier, Shimadzu LC-20AR, etc.), depending on the crude peptide loaded
  • reverse phase preparative HPLC e.g. AKTA purifier, Shimadzu LC-20AR, etc.
  • Columns with different packing materials and sizes, such as C8 or C18 semi-preparative columns or preparative columns, are selected for the amount and polarity.
  • Buffer A was 0.1% TFA in water
  • buffer B was 0.1% TFA, 100% acetonitrile. Buffer B gradient was used for elution.
  • the relevant fractions were checked by analytical HPLC using a ZORBAX 300SB-C18 (4.6X250mm, 5[mu]M) column, buffer A was 0.1% TFA in water, buffer B was 0.1% TFA, 100% acetonitrile. Flow rate 1 ml/min, detection at 210 nm wavelength. The fractions containing the target peptide with qualified purity were mixed and lyophilized to obtain the polypeptide as a white solid. The product is stored in glass vials.
  • the compounds of the present invention are linear peptides. Each amino acid can be coupled stepwise from the C-terminus to the N-terminus of the polypeptide sequence, resulting in a polypeptide backbone.
  • the process is as follows: firstly, an amino acid whose amino group is protected by a blocking group is covalently connected to the solid phase carrier, and the amino protecting group of the first amino acid is removed, so that the first amino acid is connected to the solid phase carrier. Then, the carboxyl group of the second amino acid whose amino group is blocked is activated, and reacts with the amino group of the first amino acid attached to the solid support to form a peptide bond, so that a protective group is formed on the solid support. peptides.
  • the above peptide bond formation reaction is repeated to extend the peptide chain from the C-terminus to the N-terminus until the desired peptide chain is generated. Finally, the polypeptide is cut and separated from the resin, purified and freeze-dried to obtain a polypeptide product.
  • Some compounds of the present invention are conjugated with long-acting groups or modified groups through the side chain amino group or thiol group of an amino acid whose side chain contains an amino group or a thiol group.
  • the synthesis of compound 12 includes the following steps:
  • Step A Fmoc-Lys(PG)-OH and resin are coupled to obtain Fmoc-Lys(PG)-resin, where PG is a protecting group for the amino group of the side chain of lysine;
  • Step B Fmoc-Lys(PG)-resin is coupled with amino acids or amino acid derivatives step by step to obtain the first peptide resin whose sequence is shown in the main peptide chain of compound 12;
  • Step C Remove the side chain protecting group PG of Lys at the C-terminus of the main peptide chain in the first peptide resin whose sequence is shown in the main peptide chain of compound 12, and then couple 2-(2-(2-aminoethyl) through the second stepwise step. oxy)ethoxy)acetic acid, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, ⁇ -Glu and eicosanedioic acid to obtain a second peptide resin;
  • Step D The second peptide resin was cleaved, purified and lyophilized to obtain compound 12.
  • the resin in step A can be selected from Rink Amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin and other similar resins).
  • the side chain protecting group of Lys is aloc, Mmt, Mtt, Dde or ivDde.
  • the reagent used for coupling is selected from DIC+A, B+A+C or B+C, wherein A is selected from HOAt or HOBt, and B is selected from EDC, HATU, BOP, PyBOP, PyAOP, HBTU, TBTU or DEPBT , C is selected from DIPEA, TEA, NMM or TMP.
  • the coupling agent used in the first stepwise coupling in step B and the second stepwise coupling in step C includes a condensing agent and a reaction solvent
  • the condensing agent can be a mixture of DIC and HOBt, a mixture of PyBOP, HOBt and DIEA , or a mixture of HATU, HOAt and DIEA, or a mixture of DEPBT and DIEA, or a mixture of HBTU and DIEA.
  • the reaction solvent is one, two or a mixture of two or more of DMF, DCM, NMP or DMSO.
  • step B stepwise coupling of Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc- Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Leu- OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Leu-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val -OH, Fmoc-Ala-OH, Fmo
  • the reagent used for deprotection in step C is 1-20 equivalents of morpholine (or 1-20 equivalents of phenylsilane instead of morpholine) and 0.05-3 equivalents of Pd(PPh 3 ) 4 .
  • the protecting group removal reaction can be carried out twice, each time for 10-30 minutes, preferably CH 2 Cl 2 is used as the solvent.
  • Another method to remove the Aloc protecting group is to use catalytic amounts of tetrakis(triphenylphosphine)palladium(0) and a 37:2:1 ratio of DCM, glacial acetic acid and NMM (15 mL/g resin) under argon atmosphere, Stir at room temperature for 2 hours. After reaction each gram resin was washed with 0.5% DIPEA/DMF (10 mL), 0.5% sodium diethyldithiocarbamate/DMF (3 ⁇ 10 mL), 1:1 DCM:DMF (5 ⁇ 10 mL).
  • the reagent used to remove the protecting group in step C is a hydrazine hydrate/DMF mixture.
  • a 2% (w/v) solution of hydrazine hydrate in DMF (25 mL/g resin) was prepared, added to the resin, drained after 5 minutes, and the resin was washed with DMF. The process of deprotection with 2% hydrazine hydrate/DMF and washing with DMF was repeated 3 times.
  • the reagent used for deprotection in step C is 1-2% TFA/DCM mixture.
  • step C stepwise coupling of Fmoc-8-amino-3,6-dioxaoctanoic acid (CAS No.166108-71-0), Fmoc-8-amino-3 , 6-dioxoctanoic acid, Fmoc-Glu-OtBu (CAS No. 84793-07-7) and eicosanedioic acid mono-tert-butyl ester HOOC-(CH2) 18 -COOtBu.
  • the reagents used in the cleavage in step D include one, two or a mixture of two or more of TFA and PhSMe, PhOMe, EDT, H 2 O, TIS, and PhOH.
  • the reagent used for cleavage is a mixture of TFA, anisole, methyl sulfide and EDT, and the volume ratio of TFA, anisole, methyl sulfide and EDT is 90:5:3:2.
  • the reagent used for lysis is a mixture of TFA, H 2 O and TIS, and the volume ratio is 95:2.5:2.5.
  • Some compounds of the present invention are conjugated with long-acting groups or modified groups through the side chain amino group or thiol group of an amino acid whose side chain contains an amino group or a thiol group.
  • the compound can be coupled with each amino acid step by step in the sequence from the C-terminus to the N-terminus of the polypeptide sequence, until the side chain needs to be conjugated to the amino acid residue X of a long-acting group or a modifying group.
  • the side chain protecting group of the amino acid residue X is removed to complete the synthesis of the long-acting group or the modified group.
  • the protective group of the ⁇ -amino group of the amino acid residue X is removed, and each remaining amino acid of the polypeptide main chain is sequentially coupled step by step, thereby obtaining a complete polypeptide.
  • the polypeptide is cut and separated from the resin, purified and freeze-dried to obtain a polypeptide product.
  • Step A Coupling PG1-Lys(PG2)-OH and resin to obtain PG1-Lys(PG2)-resin, PG1 is the protecting group of lysine ⁇ -amino group, PG2 is the protecting group of lysine side chain amino group group;
  • Step B Remove the side chain protecting group PG2 of the lysine in the PG1-Lys(PG2)-resin, and couple 2-(2-(2-aminoethoxy)ethoxy)acetic acid in the second stepwise step , 2-(2-(2-aminoethoxy)ethoxy)acetic acid, ⁇ -Glu and eicosanedioic acid to obtain the third peptide resin;
  • Step C removing the protective group PG1 of the ⁇ -amino group of the lysine, and coupling amino acids or amino acid derivatives step by step to obtain the fourth peptide resin whose sequence is shown in compound 12;
  • Step D The fourth peptide resin is cleaved, purified and lyophilized to obtain compound 12.
  • the resin in step A can be selected from Rink Amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin and other similar resins).
  • the side chain protecting group PG2 of Lys is Fmoc, aloc, Mmt, Mtt, Dde or ivDde.
  • the protecting group PG1 of the ⁇ -amino group of Lys is aloc, Mmt, Mtt, Dde or ivDde.
  • PG1 and PG2 must be orthogonal.
  • Examples of PG1-Lys(PG2)-OH used in the synthesis of compound 12 include Dde-Lys(Fmoc)-OH, Alloc-Lys(Fmoc)-OH, and the like.
  • For the removal method of the protecting group refer to the preparation method (1), examples or literature on solid-phase synthesis of polypeptides.
  • the reagent used for coupling is selected from DIC+A, B+A+C or B+C, wherein A is selected from HOAt or HOBt, and B is selected from EDC, HATU, BOP, PyBOP, PyAOP, HBTU, TBTU or DEPBT , C is selected from DIPEA, TEA, NMM or TMP.
  • step B stepwise coupling of Fmoc-8-amino-3,6-dioxaoctanoic acid (CAS No.166108-71-0), Fmoc-8-amino-3 , 6-dioxoctanoic acid, Fmoc-Glu-OtBu (CAS No. 84793-07-7) and eicosanedioic acid mono-tert-butyl ester HOOC-(CH2) 18 -COOtBu.
  • stepwise coupling of Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc- Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Leu- OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Leu-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val -OH, Fmoc-Ala-OH, Fmo
  • the cleavage method and the reagents used in step D are the same as the preparation method (1).
  • the present invention also includes novel intermediates and methods useful in the synthesis of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • the intermediates and compounds of the present invention can be prepared by a variety of methods known in the art. In particular, methods using chemical synthesis are exemplified in the examples below. The specific synthetic steps described for each route can be combined in various ways to prepare compounds of the invention or salts thereof. Reagents and starting materials are readily available to those of ordinary skill in the art.
  • Amino acid raw materials, condensation reagents, etc. were purchased from Gill Biochemical (Shanghai) Co., Ltd.
  • Rink Amide resin was purchased from Shangyu Poole Company and Tianjin Nankai Hecheng Technology Co., Ltd.
  • the preloaded Fmoc-Ser(tBu)-Rink Amide resin was selected, the Fmoc protecting group was removed with 20% piperidine/DMF (2 ⁇ 10 min), and the resin was washed 3 times with DMF.
  • Solid-phase peptide synthesis using Fmoc The amino acid (10 equivalents relative to the resin amino acid loading) was dissolved in DMF, then HOBT and DIC (10 equivalents relative to the resin amino acid loading) were added, mixed, and then added to the resin, and the coupling was performed at room temperature for 120 minutes. The solution in the solid phase reaction tube was evacuated and the resin was washed 3 times with DMF. So far, the coupling of one synthetic unit is completed.
  • Each synthetic unit from the C-terminal to the N-terminal of the polypeptide adopts the same coupling method, and the amino acid residues use the commonly used protective groups for Fmoc solid-phase synthesis listed in the "Solid Phase Chemical Synthesis of Polypeptides" section and the preparation method section or other suitable protection groups. Protecting group of this sequence. Boc-Tyr(tBu)-OH was used as the tyrosine at the N-terminus of the main peptide chain. The 24th amino acid Lys24 from the N-terminus used Fmoc-Lys(Dde)-OH.
  • a preloaded Fmoc-Lys(Aloc)-Rink Amide resin (eg 0.29 mmole/g) was chosen.
  • Each synthetic unit from the C-terminal to the N-terminal of the polypeptide adopts the coupling method of Example 1, and the amino acid residues except the C-terminal lysine and the N-terminal Boc-Tyr(tBu)-OH use "polypeptide solid phase chemistry".
  • the commonly used protective groups for solid-phase synthesis of Fmoc or other suitable protective groups for this sequence are listed in the "Synthetic Methods" section and the "Preparation Methods" section.
  • the C-terminal lysine side chain allyloxycarbonyl group can be removed with tetrakis(triphenylphosphine)palladium(0) and 37:2:1 ratio of DCM, glacial acetic acid and NMM (15mL/g resin) under argon atmosphere at room temperature for 2 hours. Tetrakis(triphenylphosphine)palladium(0) can be used in a catalytic amount to 1 equivalent. After reaction each gram resin was washed with 0.5% DIPEA/DMF (10 mL), 0.5% sodium diethyldithiocarbamate/DMF (3 x 10 mL), 1:1 DCM:DMF (5 x 10 mL).
  • Aloc protecting groups can also use 5-10 equivalents of morpholine (phenyl silane or 5-10 equivalents) and 0.1-0.3 equivalents of Pd (PPh 3) 4 removed.
  • the deprotection reaction can be carried out twice for 30 minutes each time, and CH 2 Cl 2 is selected as the solvent.
  • the synthesis method and steps of the lysine side chain substituent refer to Example 1.
  • Another method is to choose preloaded Fmoc-Lys(ivDde)-Rink Amide resin.
  • the synthesis method of the main peptide chain is the same as that in the previous paragraph using Fmoc-Lys(Aloc)-Rink Amide resin.
  • the C-terminal lysine side chain ivDde protecting group was removed with 2% hydrazine hydrate/DMF.
  • a 2% (w/v) solution of hydrazine hydrate in DMF (25 mL/g resin) was prepared, added to the resin, drained after 10 minutes, and the resin was washed with DMF.
  • the process of deprotection with 2% hydrazine hydrate/DMF and washing with DMF was repeated 3 times.
  • the synthetic method and procedure for this lysine side chain substituent are similar to those in Example 1.
  • the reagent used for deprotection in step C is 1-2% TFA/DCM mixture.
  • the compound whose C-terminal is lysine and the side chain amino group is connected to a long-acting group can be synthesized by the method of Example 2, or the synthetic route and method of compound 12 in the "Preparation Method" can be used.
  • Table 1 lists the calculated and measured molecular weights of some compounds of the present invention.
  • the polypeptide was dissolved in physiological saline (pH 7.4) to prepare a stock solution.
  • the polypeptide concentration in the stock solution was quantified by conventional methods such as Bradford method and UV spectrophotometric detection method.
  • PBS phosphate buffered saline
  • a more suitable injection volume for each animal is 5ml/kg body weight. The volume of injection solution that needs to be prepared can be calculated from this.
  • the in vivo efficacy of the polypeptides of the invention can be determined in any suitable animal model known in the art as well as in clinical trials.
  • the db/db mouse is a suitable animal model of diabetes.
  • the db/db mice were kept in the animal breeding room with strictly controlled environmental conditions, the temperature of the breeding room was maintained at 20-24°C, and the humidity was maintained at 40-70%.
  • the temperature and humidity in the breeding room were monitored in real time by a thermo-hygrometer, and the temperature and humidity were recorded twice a day (once in the morning and once in the afternoon).
  • the lighting in the animal breeding room is controlled by an electronic timed light-on system, with the lights on for 12 hours a day and off for 12 hours (on at 7:00 am and off at 19:00 in the afternoon).
  • the animals were housed in single cages, and the mice in each cage were provided with toys. During the experiment, animals had free access to water.
  • mice 7 weeks old were acclimated to the experimental environment for one week. Three days before the test Baseline blood glucose and body weight were recorded. Mice were randomized into groups of 6 based on three-day blood glucose and body weight. Mice were injected subcutaneously with normal saline (5ml/kg, control group) or polypeptide compounds 12 and 15 (10nmol/kg). Use Johnson &Johnson's Wenhao blood glucose meter and supporting test strips to detect blood sugar. Taking the time as the abscissa and the blood glucose value at different time points as the ordinate, draw the blood glucose curve, calculate the area under the curve (AUC), and compare the time and effect of the hypoglycemic effect of the polypeptide compound.
  • AUC area under the curve
  • the in vivo efficacy of the polypeptides of the invention can be determined in any suitable animal model known in the art.
  • Diet-induced obesity (DIO) mice are commonly used animal models of obesity, insulin resistance and hyperlipidemia.
  • 5-week-old male C57BL/6 mice were housed in an animal house with strictly controlled environmental conditions.
  • the temperature of the house was maintained at 20-24°C and the humidity was maintained at 30-70%.
  • the temperature and humidity in the breeding room were monitored in real time by a thermohygrometer, and the temperature and humidity were recorded once a day in the morning and afternoon.
  • the lighting in the animal breeding room is controlled by an electronic timed light-on system, with the lights on for 12 hours a day and off for 12 hours (on at 6:00 am and off at 18:00 pm).
  • the animals were housed in single cages, and the mice in each cage were provided with toys.
  • Animals were fed with high-fat diet from 6 weeks of age (the weight ratio of each nutrient component was protein 26.2%, carbohydrate 26.3%, fat 36.9%, and the percentages of calories provided were 20%, 20% and 60%, respectively). During the feeding process, the animals had free access to water. 26-week-old male DIO mice with an average weight of about 50 grams were selected for the experiment. Animals were acclimated to grasping and subcutaneous injection for 1 week. The body weight and food intake were measured 3 consecutive days before the experiment, and the blood glucose of the animals was measured 1 day before the experiment, and the animals were grouped according to their blood glucose and body weight, with 8 animals in each group.
  • the control group was subcutaneously injected with PBS every 2 days.
  • the liraglutide group was subcutaneously injected with liraglutide (60 nmol/kg) every 2 days.
  • Polypeptide compounds 55, 58 and 243 can all reduce the body weight of type 2 diabetic mice, with a statistically significant difference from the control group, and significantly better than liraglutide. These compounds have potential as long-acting weight loss drugs.
  • the peptide concentration in each sample was detected by LC-MS/MS method, and the mass spectrometer was (Applied Biosystems/Sciex), pharmacokinetic parameters were calculated using the non-compartmental model of WinNonLin v 6.4 (Pharsight Inc.) software.
  • the half-life of compound 12 was 9.82 ⁇ 0.49 hours, the half-life of compound 15 was 10.46 ⁇ 0.71 hours, and the half-life of the control compound was 7.93 ⁇ 0.72 hours.

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Abstract

涉及多肽化学领域，具体而言涉及一种多肽化合物及其在医疗中的用途。

Description

新型多肽及其治疗用途 技术领域
本发明涉及一种多肽化合物及其在医疗中的用途。
发明背景
代谢综合征是多种医学病症的组合，会增加发生2型糖尿病、动脉粥样硬化性血管疾病、心脏病和中风的风险。定义代谢综合征的医学参数包括糖尿病、葡萄糖耐量降低、空腹血糖升高、胰岛素抵抗、中心性肥胖、高血压、总胆固醇和甘油三酯升高、低密度胆固醇升高和高密度胆固醇降低。糖尿病包括一型糖尿病、二型糖尿病、妊娠糖尿病等。根据世界卫生组织(WHO)的数据，发达国家糖尿病患病率为5％～10％，到2030年，全世界糖尿病患者人数将比2000年翻一番。全球糖尿病未诊断人数超过50％，而且糖尿病前期的人数甚至要多于糖尿病人数。例如，中国糖尿病人数达到1.14亿，另外还有5亿人糖耐量低下、糖调节功能受损，即将成为糖尿病患者。超过半数的患者不知道自己已经得病。糖尿病的巨大危害主要在于严重的并发症和高死亡率。资料显示，糖尿病是造成下肢截肢和成人新发失明的首要病因。
肥胖是一种医学疾病，体内多余的脂肪积聚可能对健康和预期寿命产生不利影响，并且由于其在成人和儿童中的流行程度越来越高，它已经成为现代可预防的死亡原因之一。它增加了各种其它疾病，包括心脏病、2型糖尿病、阻塞性睡眠呼吸暂停、某些类型的癌症，以及骨关节炎的可能性，它通常是由多余的食物摄入量、减少的能量消耗以及遗传易感性等综合导致。在身体质量指数(BMI)相同的情况下，亚洲人比白种人的内脏脂肪含量更高，因此亚洲人比白种人存在更严重的胰岛素抵抗，亚洲体重正常的2型糖尿病患者比非糖尿病患者胰岛素敏感性显著下降。多余脂肪导致胰岛素抵抗和β细胞受损，破坏血糖调节功能。肥胖相关的多种代谢异常显著增加了心血管疾病的风险。根据临床统计，70％以上的2型糖尿病患者患病的原因是体重超标。因此，减轻糖尿病患者的体重和体脂量，是有效控制甚至逆转糖尿病发展的一个重要途径。现有小分子减肥药副作用都非常大。胰高血糖素样肽-1(GLP-1)受体激动剂类药物可以通过促进胰岛素分泌、提高胰岛素敏感度、减少胰高血糖素的释放达到控制血糖的效果。因此，GLP-1类药物适于代谢类疾病治疗，尤其是糖尿病治疗。GLP-1受体激动剂艾塞那肽、利拉鲁肽等都在动物试验和临床上显示出降低体重的效果，副作用相对较少。利拉鲁肽已经在美国被批准用于糖尿病和肥胖症治疗，成为唯一一个可以用于这两个病症的药物。
但是，现有GLP-1类药物都有胃肠道反应大的副作用。这些副作用影响了患者的用药依从度，减小了药品使用量和用户群。根据GLP-1受体的生理学机理，GLP-1药物在减肥方面作用缓慢，临床治疗肥胖症时需要使用高于糖尿病治疗的大剂量，导致胃肠道反应大的副作用更加突出。多数患者体重减轻平均不超过5％，而且停药以后体重反弹明显。
因此，对于能够降低血糖，同时降低血脂和体内脂肪含量，减轻体重的药物存在临床需求。
糖尿病患者发生心血管疾病的风险较高，因此，糖尿病患者需要严格控制血脂指标。临床研究表明，长期使用他汀类药物可能会增加使用者得糖尿病的风险。他汀类和贝特类降脂药物副作用明显，而且都有不耐受人群。非酒精性脂肪肝目前尚无疗效理想的治疗药物。本发明的多肽化合物不仅可以降血糖，而且可以显著降低甘油三脂和总胆固醇，尤其是低密度胆固醇(LDL)，有望同时解决“三高”中高血糖、高血脂两个问题，预计对使用者的心血管健康有明显益处。本发明的多肽比他汀类药物更适合糖尿病患者或糖尿病前期人群。本发明的多肽可以为这些疾病治疗提供新的选择。本发明的多肽适用于脂代谢异常引起的多种疾病，包括高脂血症、非酒精性脂肪肝等。本发明的多肽还可以用于高血压、动脉硬化、冠心病、外周动脉疾病、中风等疾病或者这些疾病的任何组合。
糖尿病患者大多数为中老年人，需要服用多种药物。这必然牵涉到药物之间的兼容和匹配。除药物交叉反应和多种药物可能导致更多的毒副作用之外，不同药物有效时间不同，服用频率 不同，也给患者增加困扰。因此，本发明的多肽不仅有利于增强疗效，降低毒副作用，而且方便患者，从而改善治疗效果。
本发明的多肽也可以像GLP-1类药物一样用于糖尿病治疗。由于这些多肽降低体重和体脂量，改善胰岛素抵抗，所以不但降糖疗效优异，对于糖尿病患者中很高比例的由于体重超标而患病的病人应该有特效。人群中很多体重超标或者肥胖的人虽然没有在医学上被定性为糖尿病人，但出现葡萄糖耐受不良、餐后血糖过度升高等糖尿病前期症状，本发明的多肽也适合糖尿病前期人群。
发明内容
在一方面，本发明涉及一种具有式(I)的肽化合物或其药学上可接受的盐或溶剂合物，
Y-aib-E-G-T-F-T-S-D-X1-S-X11-X2-X12-E-X3-X4-A-X5-X6-X13-F-X7-X8-W-L-X9-X14-G-X10(I)
其中，X1代表选自L、K、C或Y的氨基酸残基，或式(II)，或式(III)；X2代表选自Q、A、aib或Y的氨基酸残基；X3代表选自E、C或K的氨基酸残基，或式(II)，或式(III)；X4代表选自E、C或K的氨基酸残基，或式(II)，或式(III)；X5代表选自V或A的氨基酸残基，X6代表选自K、R、C或Q的氨基酸残基，或式(II)，或式(III)；X7代表选自I或V的氨基酸残基；X8代表选自E、Q、N、K、C或A的氨基酸残基，或式(II)，或式(III)；X9代表选自I、L、C或K的氨基酸残基，或式(II)，或式(III)；X10代表不存在或GPSSGAPPP，GPPSGAPPP，GPSSGKPPP，GPSSGEPPP，GPSSaibAPPP，GPSSGAPP，GPSSGAP，GPSSGA，GPSSG，GPSS，GPS，GP，G；X11代表I、C、S、K的氨基酸残基，或式(II)，或式(III)；X12代表L、C或K的氨基酸残基，或式(II)，或式(III)；X13代表L、E或D的氨基酸残基；X14代表选自A、C、K、R的氨基酸残基，或式(II)，或式(III)；所述式(II)或式(III)的结构如下：
Figure PCTCN2021104805-appb-000001
其中波浪线代表连接至相邻基团的连接点，n1为1-7的整数，
任选地，式(II)含有侧链氨基的氨基酸残基在其侧链氨基被长效基团修饰，式(III)含有侧链巯基的氨基酸残基在其侧链巯基被长效基团修饰；优选地，式(II)是赖氨酸残基，式(III)是半胱氨酸残基，
任选地，在X10的C端添加一个或两个选自S或者侧链含有氨基或者巯基的氨基酸，并且C末端氨基酸的羧基任选地被酰胺化为C末端酰胺，所述含有侧链氨基或者巯基的氨基酸残基具有式(II)或式(III)所示结构；当式(II)或式(III)为C末端氨基酸时，其羧基部分是COOH或CONH 2，优选地，式(II)是赖氨酸，式(III)是半胱氨酸；
优选地，所述长效基团具有式(IV)的结构：
O1-O2-O3-O4-O5-O6-O7-O8-    (IV)，
其中O1代表式(V)或(VI)的结构：
Figure PCTCN2021104805-appb-000002
其中n2为6-24的整数，优选10-24，进一步优选16-22；
其中波浪线代表连接至相邻基团的氨基的连接点，O2-O3-O4-O5-O6-O7-O8-代表连接体，其中O2至O8中的每一个独立地由以下氨基酸残基或长链结构中的任一个表示：α-Glu、γ-Glu、α-Asp、β-Asp、α-hGlu、δ-hGlu、Gly、Ala、β-Ala、GABA或PEG2，或者O2至O8中的一个或多个不存在，条件是O2至O8中至少有两个存在，优选地，O2至O8中含有至少一个带负电荷的部分。
根据前述任一方面的肽化合物，其中O2-O3-O4-O5-O6-O7-O8-代表选自下组的连接体：γGlu-PEG2-γGlu-、γGlu-PEG2-2×γGlu-、γGlu-PEG2-、γGlu-2×PEG2-、γGlu-3×PEG2-、γGlu-PEG2-γGlu-PEG2-、γGlu-2×PEG2-γGlu-、γGlu-2×PEG2-2×γGlu-、2×γGlu-、2×γGlu-PEG2-、2×γGlu-PEG2-γGlu-、2×γGlu-PEG2-γGlu-PEG2-、2×γGlu-2×PEG2-、2×γGlu-2×PEG2-γGlu-、2×γGlu-2×PEG2-2×γGlu-。
根据前述方面的肽化合物，在一些实施方案中，其中O2-O3-O4-O5-O6-O7-O8-代表选自下组的连接体γGlu-PEG2-、γGlu-2×PEG2-、γGlu-3×PEG2-，O1代表式(V)或(VI)的结构。
根据前述方面的肽化合物，在一些实施方案中，其中O2-O3-O4-O5-O6-O7-O8-代表选自下组的连接体γGlu-PEG2-、γGlu-2×PEG2-、γGlu-3×PEG2-，O1代表式(V)的结构。
根据前述方面的肽化合物，在一些实施方案中，其中O2-O3-O4-O5-O6-O7-O8-代表选自下组的连接体γGlu-2×PEG2-、γGlu-3×PEG2-，O1代表式(V)的结构。
根据前述方面的肽化合物，在一些实施方案中，其中O2-O3-O4-O5-O6-O7-O8-代表连接体γGlu-2×PEG2-，O1代表式(V)的结构。
根据前述方面的肽化合物，在一些实施方案中，其中O2-O3-O4-O5-O6-O7-O8-代表连接体γGlu-2×PEG2-，O1代表式(V)的结构，其中n2为16-22的整数。
在一些实施方案中，赖氨酸侧链氨基缀合长效基团，本申请中该分子结构简称为K(x18)，具有式(VII)的结构：
Figure PCTCN2021104805-appb-000003
在一些实施方案中，赖氨酸侧链缀合长效基团，本申请中该分子结构简称为K(x20)，具有式(VIII)的结构：
Figure PCTCN2021104805-appb-000004
其中波浪线代表连接至相邻氨基酸残基的连接点。
任选地，X10的C端添加的含有侧链巯基的氨基酸在其侧链巯基被式(IV)的长效基团修饰，任选地，在C端氨基酸的侧链巯基和长效基团之间可以根据需要添加能够与巯基反应生成共价键的反应基团。
在一些实施方案中，含有侧链巯基的氨基酸的侧链巯基与长效基团之间的连接关系是：含有侧链巯基的氨基酸的侧链巯基-巯基反应基团-可选的连接基团L-长效基团。
在一些实施方案中，所述含有侧链巯基的氨基酸的侧链巯基通过与迈克尔反应受体(例如马来酰亚胺或乙烯基砜)或硫醇反应性基团(例如碘乙酸或溴乙酸)反应后与连接基团L一端连接，优选地，所述连接基团L另一端进一步与式IV的长效基团形成共价键连接。
在一些实施方式中，所述连接基团L是-(CH 2) n3-和-(CH 2CH 2O) n4-根据结构需要排列组合，通过共价键连接在一起形成的长链；或者-(CH 2) n3-、-(CH 2CH 2O) n4-的一端或者两端任选地包含氨基或羧基，通过酰胺键连接在一起形成的长链，例如，所述连接基团L选自-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NH-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-CO-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NHCO-(CH 2) n8-，-NH-(CH 2) n5-(CH 2CH 2O) n6- (CH 2) n7-NHCO-(CH 2) n8-NH-或其任意组合，其中n3、n4、n5、n6、n7、n8各自是0至10的整数，例如0、1、2、3、4、5、6、7、8、9、10。
在一些实施方式中，L是-NH-CH 2-(CH 2CH 2O) 3-(CH 2) 3-NH-。
在一些实施方式中，迈克尔反应受体或硫醇反应性基团与连接基团L连接的非限制性说明性实例包括
Figure PCTCN2021104805-appb-000005
以上示例性迈克尔反应受体或硫醇反应性基团与含有侧链巯基的氨基酸的侧链巯基反应后的结构如下：
Figure PCTCN2021104805-appb-000006
波浪线为与式(IV)的长效基团的连接点，例如，连接到O8上。*为含有侧链巯基的氨基酸的侧链巯基与氨基酸其它部分的连接点。
任选地，X10代表的多肽片段中的任何一个氨基酸可以被侧链含有氨基或者巯基的氨基酸取代，所述氨基酸具有式(II)或式(III)结构。任选地，含有侧链氨基的氨基酸在其侧链氨基被长效基团修饰，优选地，所述长效基团具有式(IV)的结构；任选地，含有侧链巯基的氨基酸在其侧链巯基被长效基团修饰，优选地，所述长效基团具有式(IV)的结构，任选地，侧链巯基和长效基团之间可以根据需要添加能够与巯基反应生成共价键的反应基团。
在一些实施方案中，半胱氨酸侧链巯基缀合长效基团，本申请中该分子结构简称为C(x18)，具有式(IX)的结构：
Figure PCTCN2021104805-appb-000007
在一些实施方案中，半胱氨酸侧链巯基缀合长效基团，本申请中该分子结构简称为C(x20)，具有式(X)的结构：
Figure PCTCN2021104805-appb-000008
其中波浪线代表连接至相邻基团的连接点。
任选地，X10代表的多肽片段GPPSGAPPP，GPSSGKPPP，GPSSGEPPP，GPSSaibAPPP可以从片段C末端向片段N末端缩减1，2，3，4，5，6，7，8个氨基酸。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y。根据前述任一方面的肽化合物，在一些实施方案中，X1是K。根据前述任一方面的肽化合物，在一些实施方案中，X1是C。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q。根据前述任一方面的肽化合物，在一些实施方案中，X2是Y。根据前述任一方面的肽化合物，在一些实施方案中，X2是A。根据前述任一方面的肽化合物，在一些实施方案中，X2是Aib。
根据前述任一方面的肽化合物，在一些实施方案中，X3是E。根据前述任一方面的肽化合物，在一些实施方案中，X3是K。根据前述任一方面的肽化合物，在一些实施方案中，X3是C。
根据前述任一方面的肽化合物，在一些实施方案中，X4是E。根据前述任一方面的肽化合物，在一些实施方案中，X4是K。根据前述任一方面的肽化合物，在一些实施方案中，X4是C。
根据前述任一方面的肽化合物，在一些实施方案中，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X5是A。
根据前述任一方面的肽化合物，在一些实施方案中，X6是K。根据前述任一方面的肽化合物，在一些实施方案中，X6是R。根据前述任一方面的肽化合物，在一些实施方案中，X6是Q。根据前述任一方面的肽化合物，在一些实施方案中，X6是C。
根据前述任一方面的肽化合物，在一些实施方案中，X7是I。根据前述任一方面的肽化合物，在一些实施方案中，X7是V。
根据前述任一方面的肽化合物，在一些实施方案中，X8是E。根据前述任一方面的肽化合物，在一些实施方案中，X8是N。根据前述任一方面的肽化合物，在一些实施方案中，X8是Q。根据前述任一方面的肽化合物，在一些实施方案中，X8是A。根据前述任一方面的肽化合物，在一些实施方案中，X8是K。根据前述任一方面的肽化合物，在一些实施方案中，X8是C。
根据前述任一方面的肽化合物，在一些实施方案中，X9是I。根据前述任一方面的肽化合物，在一些实施方案中，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X9是K。根据前述任一方面的肽化合物，在一些实施方案中，X9是Aib。根据前述任一方面的肽化合物，在一些实施方案中，X9是V。
根据前述任一方面的肽化合物，在一些实施方案中，X10不存在。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPPSK。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPPSC。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPPC。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPPP。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAPP。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGAP。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSGA。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSSG。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPSS。根据前述任一方面的肽化合物，在一些实施方案中，X10是GPS。根据前述任一方面的肽化合物，在一些实施方案中，X10是GP。根据前述任一方面的肽化合物，在一些实施方案中，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGAPPPC。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGAPPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGAPP。根据前述任一方面的肽化合物，在一 些实施方案中，X1是L，X10是GPSSGAP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSGA。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSSG。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPSS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是GP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAPPPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAPPPK。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAPPPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAPPPK。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAPPPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAPPPK。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAPPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGAP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSGA。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSSG。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPSS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是GP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAPPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGAP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSGA。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSSG。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPSS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是GP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X9是K。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAPPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAPP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGAP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSGA。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSSG。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPSS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GPS。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是GP。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X9是K。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Y，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAPPPC。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAPPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGAP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSGA。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSSG。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPSS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是GP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAPPPC。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAPPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGAP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSGA。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSSG。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPSS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是GP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAPPPC。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAPPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAPP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGAP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSGA。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSSG。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPSS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是GP。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X10是G。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X9是K。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X9是K。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Y，X9是K。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是 V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X9是L，X10是GPSSGAPPPS。根据前述任一 方面的肽化合物，在一些实施方案中，X2是A，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X2是A，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X2是aib，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案 中，X1是L，X2是Q，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X9是L，X10是GPSSGAPPPS。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPK。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是V，X9是L，X10是GPSSGAPPPC。
根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Q。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Aib。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y。
根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X3是K，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X7是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X7是V，X8是N，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X7是V，X8是N，X9是I。根据前述任一方面的肽化合物，在一些实施方案中，X1是Y，X2是Y，X3是K，X5是V，X7是I，X8是E，X9是L。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X9是I。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X9是L。根据前述任一方面 的肽化合物，在一些实施方案中，X1是L，X2是Q，X3是K，X5是V，X7是I，X8是E，X9是L。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A，X3是K，X5是V，X7是I，X8是E，X9是L。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X9是L。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是aib，X3是K，X5是V，X7是I，X8是E，X9是L。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X4是E，X9是I或L,X11是I，X12是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X4是E，X5是V，X9是I或L,X11是I，X12是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X3是K，X4是E，X5是V，X9是I或L,X11是I，X12是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A或aib，X3是K，X4是E，X5是V，X9是I或L,X11是I，X12是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A或aib，X3是K，X4是E，X5是V，X7是I，X9是I或L,X11是I，X12是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A或aib，X3是K，X4是E，X5是V，X6是R，X7是I，X9是I或L,X11是I，X12是L，X13是L，X14是A。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A或aib，X3是K，X4是E，X5是V，X6是R，X7是I，X8是E，X9是I或L,X11是I，X12是L，X13是L，X14是A。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X3是K，X4是E，X5是V，X6是R，X7是I，X8是E，X9是I或L,X11是I，X12是L，X13是L，X14是A。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A或aib，X3是K，X4是E，X5是V，X6是R，X7是I，X8是E，X9是I或L,X11是I，X12是L，X13是L，X14是A，X10选自GPSSGAPPP，GPPSGAPPP，GPSSGKPPP，GPSSGEPPP，GPSSaibAPPP，GPSSGAPP，GPSSGAP，GPSSGA，GPSSG，GPSS，GPS，GP，或G，或在X10的C端添加一个或两个选自S或者侧链含有氨基或者巯基的氨基酸，并且C末端氨基酸的羧基任选地被酰胺化为C末端酰胺，所述含有氨基或者巯基的氨基酸残基具有式(II)或式(III)所示结构；当式(II)或式(III)为C末端氨基酸时，其羧基部分是COOH或CONH 2，优选地，式(II)是赖氨酸，式(III)是半胱氨酸。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Y。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Y，X5是V。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是Y，X3是K，X5是V。
根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A、aib或Y，X4是E，X11是I或S。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A、aib或Y，X4是E，X11是I。根据前述任一方面的肽化合物，在一些实施方案中，X1是L，X2是A、aib或Y，X3是K，X4是E，X11是I。
根据前述任一方面的肽化合物，在一些实施方案中，X2是Q，X9是K，X10及C末端氨基酸组成的序列不是GPSSGAPPPS或GPSSGAPPPSK。
根据前述任一方面的肽化合物，在一些实施方案中，X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)。根据前述任一方面的肽化合物，在一些实施方案中， X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)，且至少一个式(II)或式(III)侧链缀合长效基团或修饰基团。根据前述任一方面的肽化合物，在一些实施方案中，X1、X4、X8、X11、X12、X14中至少有一个是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)，且X10、C末端X10及C末端氨基酸组成的序列不包含式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)，且X10及C末端X10及C末端氨基酸组成的序列不是GPSSGAPPPK、GPSSGAPPPC、GPSSGAPPPSC或GPSSGAPPPSK。
根据前述任一方面的肽化合物，在一些实施方案中，X2代表选自A、aib或Y的氨基酸残基，X12是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X1是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X1是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X1是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X3是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X3是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X3是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X4是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X4是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X4是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X6是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X6是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X6是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X8是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X8是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X8是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X9是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X9是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X9是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X11是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X11是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X11是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X12是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X12是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X12是K(x20)。
根据前述任一方面的肽化合物，在一些实施方案中，X14是式(II)或式(III)。
根据前述任一方面的肽化合物，在一些实施方案中，X14是K(x18)。
根据前述任一方面的肽化合物，在一些实施方案中，X14是K(x20)。
根据前述任一方面的肽化合物，其中所述肽化合物不是PCT申请号为PCT/CN2020/070697中所述的肽化合物。
根据前述任一方面的肽化合物，其中所述肽化合物选自：
化合物1.
Figure PCTCN2021104805-appb-000009
化合物2.
Figure PCTCN2021104805-appb-000010
化合物3.
Figure PCTCN2021104805-appb-000011
化合物4.
Figure PCTCN2021104805-appb-000012
化合物5.
Figure PCTCN2021104805-appb-000013
化合物6.
Figure PCTCN2021104805-appb-000014
化合物7.
Figure PCTCN2021104805-appb-000015
化合物8.
Figure PCTCN2021104805-appb-000016
化合物9.
Figure PCTCN2021104805-appb-000017
化合物10.
Figure PCTCN2021104805-appb-000018
化合物11.
Figure PCTCN2021104805-appb-000019
化合物12.
Figure PCTCN2021104805-appb-000020
化合物13.
Figure PCTCN2021104805-appb-000021
化合物14.
Figure PCTCN2021104805-appb-000022
化合物15.
Figure PCTCN2021104805-appb-000023
化合物16.
Figure PCTCN2021104805-appb-000024
化合物17.
Figure PCTCN2021104805-appb-000025
化合物18.
Figure PCTCN2021104805-appb-000026
化合物19.
Figure PCTCN2021104805-appb-000027
化合物20.
Figure PCTCN2021104805-appb-000028
化合物21.
Figure PCTCN2021104805-appb-000029
化合物22.
Figure PCTCN2021104805-appb-000030
化合物23.
Figure PCTCN2021104805-appb-000031
化合物24.
Figure PCTCN2021104805-appb-000032
化合物25.
Figure PCTCN2021104805-appb-000033
化合物26.
Figure PCTCN2021104805-appb-000034
化合物27.
Figure PCTCN2021104805-appb-000035
化合物28.
Figure PCTCN2021104805-appb-000036
化合物29.
Figure PCTCN2021104805-appb-000037
化合物30.
Figure PCTCN2021104805-appb-000038
化合物31.
Figure PCTCN2021104805-appb-000039
化合物32.
Figure PCTCN2021104805-appb-000040
化合物33.
Figure PCTCN2021104805-appb-000041
化合物34.
Figure PCTCN2021104805-appb-000042
化合物35.
Figure PCTCN2021104805-appb-000043
化合物36.
Figure PCTCN2021104805-appb-000044
化合物37.
Figure PCTCN2021104805-appb-000045
化合物38.
Figure PCTCN2021104805-appb-000046
化合物39.
Figure PCTCN2021104805-appb-000047
化合物40.
Figure PCTCN2021104805-appb-000048
化合物41.
Figure PCTCN2021104805-appb-000049
化合物42.
Figure PCTCN2021104805-appb-000050
化合物43.
Figure PCTCN2021104805-appb-000051
化合物44.
Figure PCTCN2021104805-appb-000052
化合物45.
Figure PCTCN2021104805-appb-000053
化合物46.
Figure PCTCN2021104805-appb-000054
化合物47.
Figure PCTCN2021104805-appb-000055
化合物48.
Figure PCTCN2021104805-appb-000056
化合物49.
Figure PCTCN2021104805-appb-000057
化合物50.
Figure PCTCN2021104805-appb-000058
化合物51.
Figure PCTCN2021104805-appb-000059
化合物52.
Figure PCTCN2021104805-appb-000060
化合物53.
Figure PCTCN2021104805-appb-000061
化合物54.
Figure PCTCN2021104805-appb-000062
化合物55.
Figure PCTCN2021104805-appb-000063
化合物56.
Figure PCTCN2021104805-appb-000064
化合物57.
Figure PCTCN2021104805-appb-000065
化合物58.
Figure PCTCN2021104805-appb-000066
化合物59.
Figure PCTCN2021104805-appb-000067
化合物60.
Figure PCTCN2021104805-appb-000068
化合物61.
Figure PCTCN2021104805-appb-000069
化合物62.
Figure PCTCN2021104805-appb-000070
化合物63.
Figure PCTCN2021104805-appb-000071
化合物64.
Figure PCTCN2021104805-appb-000072
化合物65.
Figure PCTCN2021104805-appb-000073
化合物66.
Figure PCTCN2021104805-appb-000074
化合物67.
Figure PCTCN2021104805-appb-000075
化合物68.
Figure PCTCN2021104805-appb-000076
化合物69.
Figure PCTCN2021104805-appb-000077
化合物70.
Figure PCTCN2021104805-appb-000078
化合物71.
Figure PCTCN2021104805-appb-000079
化合物72.
Figure PCTCN2021104805-appb-000080
化合物73.
Figure PCTCN2021104805-appb-000081
化合物74.
Figure PCTCN2021104805-appb-000082
化合物75.
Figure PCTCN2021104805-appb-000083
化合物76.
Figure PCTCN2021104805-appb-000084
化合物77.
Figure PCTCN2021104805-appb-000085
化合物78.
Figure PCTCN2021104805-appb-000086
化合物79.
Figure PCTCN2021104805-appb-000087
化合物80.
Figure PCTCN2021104805-appb-000088
化合物81.
Figure PCTCN2021104805-appb-000089
化合物82.
Figure PCTCN2021104805-appb-000090
化合物83.
Figure PCTCN2021104805-appb-000091
化合物84.
Figure PCTCN2021104805-appb-000092
化合物85.
Figure PCTCN2021104805-appb-000093
化合物86.YaibEGTFTSDLSK(x20)ALEKEAVRLFIEWLIAGGPSSGA-NH 2
化合物87.YaibEGTFTSDLSIQLEEEAVRLFIEWLIK(x20)GGPSSGAPPPS-NH 2
化合物88.YaibEGTFTSDLSK(x18)ALEKEAVRLFIEWLKAGGPSS-NH2
化合物89.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x18)-NH 2
化合物90.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGA-NH 2
化合物91.YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLIAGGPSS-NH2
化合物92.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGK(x18)-NH 2
化合物93.YaibEGTFTSDLSK(x20)QLEKEAVQDFVNWLLAGGPSSGAPPPS-NH 2
化合物94.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH2
化合物95.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x20)-NH 2
化合物96.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGAPPPS-NH 2
化合物97.YaibEGTFTSDLSK(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
化合物98.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSK(x20)-NH 2
化合物99.YaibEGTFTSDLSIaibK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物100.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSS-NH 2
化合物101.YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物102.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x20)-NH 2
化合物103.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x20)GGPSSGAPPPS-NH 2
化合物104.YaibEGTFTSDLSIAC(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物105.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH 2
化合物106.YaibEGTFTSDLSIQLEKEAVKLFVNWLIK(x20)GGPSSGAPPPS-NH 2
化合物107.YaibEGTFTSDLSIAC(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物108.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSS-NH2
化合物109.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC(x20)-NH 2
化合物110.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
化合物111.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGA-NH2
化合物112.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH2
化合物113.YaibEGTFTSDLSIQLEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH 2
化合物114.YaibEGTFTSDK(x18)SIYLEKEAVRLFIEWLIAGGPSSGA-NH 2
化合物115.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
化合物116.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC(x18)-NH 2
化合物117.YaibEGTFTSDK(x20)SIALEEEAVQDFVQWLIAGGPSSGAPPPS-NH 2
化合物118.YaibEGTFTSDLSC(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
化合物119.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGK(x20)-NH 2
化合物120.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSSGA-NH 2
化合物121.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSS-NH2
化合物122.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPS-NH 2
化合物123.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x20)-NH 2
化合物124.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPS-NH 2
化合物125.YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSS-NH2
化合物126.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x18)-NH 2
化合物127.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物128.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSG-NH 2
化合物129.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
化合物130.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAK(x18)-NH 2
化合物131.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物132.YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSS-NH 2
化合物133.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPS-NH2
化合物134.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPC(x18)-NH 2
化合物135.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGA-NH 2
化合物136.YaibEGTFTSDLSIaibLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物137.YaibEGTFTSDLSIALEC(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物138.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAK(x20)-NH 2
化合物139.YaibEGTFTSDLSIYK(x20)EKEAVRLFIEWLKAGGPSSGA-NH 2
化合物140.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物141.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPSSG-NH 2
化合物142.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPK(x18)-NH 2
化合物143.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
化合物144.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSS-NH 2
化合物145.YaibEGTFTSDK(x20)SIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物146.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x20)-NH 2
化合物147.YaibEGTFTSDC(x18)SIaibLEKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物148.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物149.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
化合物150.YaibEGTFTSDLSIYK(x18)EKEAVRLFIEWLLAGGPS-NH2
化合物151.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
化合物152.YaibEGTFTSDC(x20)SIALEKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物153.YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSSGA-NH 2
化合物154.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
化合物155.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x18)-NH 2
化合物156.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSSGA-NH 2
化合物157.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x18)-NH 2
化合物158.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSS-NH2
化合物159.YaibEGTFTSDLSIAK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物160.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x18)-NH 2
化合物161.YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGA-NH 2
化合物162.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGA-NH2
化合物163.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x20)-NH 2
化合物164.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物165.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSG-NH 2
化合物166.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSSGA-NH 2
化合物167.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSSGA-NH 2
化合物168.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSS-NH 2
化合物169.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAPP-NH 2
化合物170.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSS-NH 2
化合物171.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPS-NH 2
化合物172.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSS-NH2
化合物173.YaibEGTFTSDLSC(x20)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
化合物174.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPS-NH2
化合物175.YaibEGTFTSDLSIALEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物176.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x20)-NH 2
化合物177.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGA-NH2
化合物178.YaibEGTFTSDLSIQLEEEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
化合物179.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
化合物180.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x18)-NH 2
化合物181.YaibEGTFTSDLSIaibLEK(x18)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物182.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSS-NH 2
化合物183.YaibEGTFTSDLSIALEC(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物184.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
化合物185.YaibEGTFTSDYSIYLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物186.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x18)-NH 2
化合物187.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物188.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLIAGGPSSGAPPPS-NH 2
化合物189.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSG-NH 2
化合物190.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSSGA-NH 2
化合物191.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
化合物192.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
化合物193.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSS-NH 2
化合物194.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物195.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSS-NH 2
化合物196.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSSGA-NH 2
化合物197.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
化合物198.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAP-NH 2
化合物199.YaibEGTFTSDLSIALEKEAVK(x20)LFIEWLKAGGPSSGAPPPS-NH 2
化合物200.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSGAPPPC(x20)-NH 2
化合物201.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
化合物202.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSS-NH2
化合物203.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH 2
化合物204.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGA-NH 2
化合物205.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSS-NH 2
化合物206.YaibEGTFTSDLSIALEKEAVK(x20)DFVNWLLAGGPSSGAPPPS-NH 2
化合物207.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x20)-NH 2
化合物208.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGA-NH 2
化合物209.YaibEGTFTSDLSIALEKEAVC(x18)LFIEWLIAGGPSSGAPPPS-NH 2
化合物210.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
化合物211.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSG-NH 2
化合物212.YaibEGTFTSDLSIALEKEAVC(x20)LFIEWLIAGGPSSGAPPPS-NH 2
化合物213.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSS-NH 2
化合物214.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
化合物215.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSS-NH 2
化合物216.YaibEGTFTSDLSIALEKC(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物217.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH 2
化合物218.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSS-NH 2
化合物219.YaibEGTFTSDYSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
化合物220.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLKAGGPS-NH 2
化合物221.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSSGA-NH 2
化合物222.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSS-NH 2
化合物223.YaibEGTFTSDLSIALEKC(x18)AVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物224.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPS-NH 2
化合物225.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH 2
化合物226.YaibEGTFTSDLSIaibLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物227.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLLAGGPSSG-NH 2
化合物228.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSS-NH 2
化合物229.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSSGA-NH 2
化合物230.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSS-NH 2
化合物231.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGA-NH 2
化合物232.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSS-NH 2
化合物233.YaibEGTFTSDLSIALEKEAVKEFIAWLK(x20)AGGPSSGAPPPS-NH 2
化合物234.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPS-NH 2
化合物235.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSGAPPPS-NH 2
化合物236.YaibEGTFTSDLSIYLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物237.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
化合物238.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
化合物239.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSS-NH 2
化合物240.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH 2
化合物241.YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSG-NH 2
化合物242.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
化合物243.YaibEGTFTSDLSIQLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
化合物244.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
化合物245.YaibEGTFTSDYSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
化合物246.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPS-NH 2
化合物247.YaibEGTFTSDLSIALEK(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH 2
化合物248.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
化合物249.YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPSSG-NH 2
化合物250.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
化合物251.YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPS-NH 2
化合物252.YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
化合物253.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
化合物254.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
化合物255.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLIAGGPSSGA-NH 2
化合物256.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSG-NH 2
化合物257.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLIAGGPSS-NH 2
化合物258.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
化合物259.YaibEGTFTSDLSIQLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
化合物260.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH 2
化合物261.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLIAGGPS-NH 2
化合物262.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
化合物263.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSG-NH 2
化合物264.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPP-NH 2
化合物265.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGA-NH 2
化合物266.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH 2
化合物267.YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSSGA-NH 2
化合物268.YaibEGTFTSDLSIQLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
化合物269.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH 2
化合物270.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAP-NH 2
化合物271.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH 2
化合物272..YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x18)AGGPSS-NH 2
化合物273.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAK(x20)-NH 2
化合物274..YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
化合物275.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGA-NH 2
化合物276.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
化合物277.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSS-NH 2
化合物278.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH2
化合物279.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPSSG-NH 2
化合物280.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSGAPPPS-NH 2
化合物281.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSS-NH 2
化合物282.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
化合物283.YaibEGTFTSDLSIaibLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH 2
化合物284.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
化合物285.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
化合物286.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGA-NH 2
化合物287.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
化合物288.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
化合物289.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
化合物290.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSSGA-NH 2
化合物291.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSSGA-NH 2
化合物292.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH 2
化合物293.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSSGA-NH 2
化合物294.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSS-NH 2
化合物295.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSS-NH 2
化合物296.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
化合物297.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPP-NH2
化合物298.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
化合物299.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPS-NH 2
化合物300.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH 2
化合物301.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
化合物302.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGA-NH 2
化合物303.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSSGA-NH 2
化合物304.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
化合物305.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH 2
化合物306.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSG-NH 2
化合物307.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
化合物308.YaibEGTFTSDK(x20)SIaibLEKEAVKEFIAWLLAGGPSSGAPPPS-NH 2
化合物309.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGK(x20)-NH 2
化合物310.YaibEGTFTSDLSK(x18)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
化合物311.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
化合物312.YaibEGTFTSDLSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
化合物313.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGAPPPS-NH 2
化合物314.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSGAPPPS-NH 2
化合物315.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSS-NH 2
化合物316.YaibEGTFTSDLSIQLEKEAVQDFVNWLIK(x18)GGPSSGAPPPS-NH 2
化合物317.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSK(x18)-NH 2
化合物318.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
化合物319.YaibEGTFTSDLSIQLEEEAVK(x18)EFIAWLLKGG-NH 2
化合物320.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPK(x18)-NH 2
化合物321.YaibEGTFTSDLSIQLEKEAVKLFVNWLK(x20)AGGPSSGAPPPS-NH 2
化合物322.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAP-NH 2
化合物323.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH 2
化合物324.YaibEGTFTSDLSIQLEKEAVQDFVNWLK(x18)AGGPSSGAPPPS-NH 2
化合物325.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSK(x18)-NH 2
化合物326.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
化合物327.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGA-NH 2
化合物328.YaibEGTFTSDK(x18)SIQLEKEAVRLFIEWLLAGGPSS-NH 2
化合物329.YaibEGTFTSDLSIALEKEAVRLFIEWLK(x18)AGGPSS-NH 2
化合物330.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH 2
化合物331.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
化合物332.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSS-NH 2
化合物333.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSS-NH 2
化合物334.Y(aib)EGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSK(x18)-NH 2
化合物335.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSS-NH 2
化合物336.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAP-NH 2
化合物337.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH 2
化合物338.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
化合物339.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSS-NH 2
化合物340.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPSSGA-NH 2
化合物341.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
化合物342.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
化合物343.YaibEGTFTSDLSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
化合物344.YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLLAGGPSSGA-NH 2
化合物345.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPS-NH 2
化合物346.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPP-NH 2
化合物347.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
化合物348.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAPPK(x20)-NH 2
化合物349.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPP-NH 2
化合物350.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLKAGGPSK(x18)-NH 2
化合物351.Y(aib)EGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGK(x20)-NH 2
化合物352.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSS-NH 2
化合物353.YaibEGTFTSDLSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
化合物354.YaibEGTFTSDLSSYLEKEAVRLFVQWLKRGGPSSGAPC(x20)-NH 2
化合物355.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
化合物356.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLIAGGPSSGAP-NH 2
化合物357.YaibEGTFTSDLSIYLEEEAAK(x18)EFIAWLLKGGP-NH 2
根据前述任一方面的肽化合物，其中所述肽化合物只包含天然氨基酸。
在一方面本发明涉及一种药物组合物，其包含前述的肽化合物或其药学上可接受的盐或溶剂合物，以及药学上可接受的载体或赋形剂。
在一方面本发明涉及治疗或预防下列疾病或状况的方法：葡萄糖耐量受损(IGT)、高血糖症、1型糖尿病、2型糖尿病、肥胖症、代谢综合征和神经退行性疾病，特别是用于延缓或预 防2型糖尿病中的疾病进展，延缓从葡萄糖耐量受损到2型糖尿病的进展；延缓从2型糖尿病到需要胰岛素的糖尿病的进展；治疗代谢综合征，用于调节食欲，诱发饱足感，减少食物摄入，增加能量消耗，治疗肥胖症或预防超重；预防减肥成功后的体重反弹；治疗与超重或肥胖症相关的疾病或状态；治疗贪食症；治疗暴食；治疗血脂异常、动脉粥样硬化、高血压、冠心病、β-阻断剂中毒；非酒精性脂肪性肝病(NAFLD,non-alcoholic fatty liver disease)(可分为单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化)；用于抑制胃肠道的运动，用于与使用如X射线、CT和NMR扫描的技术的胃肠道调查联用；所述方法包括对患者施用有效量的前述任一方面的肽化合物或其药学上可接受的盐或溶剂合物或药物组合物。
在一方面本发明涉及前述任一方面的肽化合物或其药学上可接受的盐或溶剂合物或药物组合物在制备用于降血糖或治疗糖尿病的药物中的用途。
在一方面本发明涉及前述任一方面的肽化合物或其药学上可接受的盐或溶剂合物或药物组合物在制备用于减肥的药物中的用途。
在一方面本发明涉及前述任一方面的肽化合物或其药学上可接受的盐或溶剂合物或药物组合物在制备用于降血脂的药物中的用途。优选降低选自下列的血脂成分：胆固醇、甘油三酯、游离脂肪酸、低密度脂蛋白胆固醇。
在一方面本发明涉及前述任一方面的肽化合物的制备方法，其中所述制备方法是通过化学合成的方法。
本发明人通过对GLP-1受体激动剂肽衍生物进行一系列结构改造，包括对特定氨基酸进行选择，或在肽的C末端引入新氨基酸，或对肽的C末端氨基酸残基进行取代，并将独特的长效基团通过多肽C末端的半胱氨酸残基侧链巯基或赖氨酸残基的侧链氨基链接到多肽上，得到了一类全新的肽化合物。取得了预料不到的技术效果。
附图说明
图1：本发明化合物12和15降低db/db小鼠的血糖。
图2：本发明化合物55、58和243降低DIO小鼠体重。
具体实施方式
除非另外说明，下述定义适用于本发明全文。未定义的术语可以根据行业内约定俗成的定义理解。
“氨基酸”指同时包含氨基和羧基官能团的分子，α-氨基酸的氨基和羧基连接在同一个碳原子(α碳)上。α碳可以另外有1-2个有机取代基。氨基酸包含L和D同分异构体和消旋混合物。如无特别说明，本发明中多肽序列中的氨基酸残基都是L同分异构体即L-氨基酸，D-氨基酸在氨基酸名称或缩写前加小写字母“d”表示，如dK。
本发明的氨基酸序列含有用于天然存在的氨基酸的常规单字母或三字母代码，以及用于其它氨基酸的普遍承认的三字母代码，如Tic(1,2,3,4-四氢异喹啉-3-羧酸)、Aib(α-氨基异丁酸)或GABA(γ-氨基丁酸)。常用分子结构的缩写代码包括：
hGlu为高谷氨酸；
α-hGlu为-HNCH(CO-)CH 2CH 2CH 2COOH的L同分异构体；
δ-hGlu为-HNCH(COOH)CH 2CH 2CH 2CO-的L同分异构体；
α-Glu为-HNCH(CO-)CH 2CH 2COOH的L同分异构体；
γ-Glu或gGlu为-HNCH(COOH)CH 2CH 2CO-的L同分异构体；
α-Asp为-HNCH(CO-)CH 2COOH的L同分异构体；
β-Asp为-HNCH(COOH)CH 2CO-的L同分异构体；
β-Ala为-HN-CH 2-CH 2-COOH；
PEG2为2-(2-(2-氨基乙氧基)乙氧基)乙酸(CAS No.134978-97-5)。
本发明中多肽的氨基酸组成可以改变而基本不影响其生物活性。例如，一个多肽序列可以包含一个或多个保守氨基酸取代。保守氨基酸取代是一个氨基酸残基被另一个有相似侧链的氨基酸残基取代。文献中根据氨基酸残基侧链的性质对氨基酸残基进行分类。含有碱性侧链氨基 酸残基包括赖氨酸、精氨酸、组氨酸；包含酸性侧链及其酰胺侧链氨基酸残基包括天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺；小脂肪族、非极性或弱极性侧链氨基酸残基包括甘氨酸、丙氨酸、苏氨酸、丝氨酸、脯氨酸；大脂肪族、非极性侧链氨基酸残基包括亮氨酸、异亮氨酸、缬氨酸；芳香族氨基酸残基包括苯丙氨酸、色氨酸、酪氨酸；含硫侧链氨基酸残基包括半胱氨酸、甲硫氨酸。
在一些实施方案中，所述衍生物包含含有亲脂性部分和可选的带1-3个负电荷的部分的取代基，其中所述带负电荷的部分中的一个在亲脂性部分的远端。在一些实施方案中，所述取代基连接在序列C末端的氨基酸的侧链上。如果序列C末端是赖氨酸，就是连接在赖氨酸残基的ε氨基上。
如本文所用，“表达载体”包括能够表达DNA的载体，所述DNA与诸如启动子区的能够影响这类DNA片段表达的调控序列可操作地连接。这类额外的片段可以包括启动子和终止子序列，并且任选地可以包括一个或多个复制起点、一个或多个选择标记、增强子、多腺苷酸化信号等。表达载体一般来源于质粒或病毒DNA，或者可以包含这两者的元件。因此，表达载体指重组DNA或RNA构建体，例如质粒、噬菌体、重组病毒或其他载体，当引入适当的宿主细胞时，导致克隆DNA的表达。适当的表达载体是本领域技术人员公知的，并且包括在真核细胞和/或原核细胞中可复制的表达载体以及保持游离的表达载体或者整合入宿主细胞基因组的表达载体。在一个实施方案中，即当化合物包含遗传学编码的氨基酸残基时，本发明进一步提供编码所述化合物的核酸(其可以是DNA或RNA)、包含这种核酸的载体以及含有这种核酸或表达载体的宿主细胞。
如本文所用，术语“治疗”包括抑制、减缓、停止或逆转现有症状或病患的进展或严重程度。因此，治疗包括预防、治疗和/或治愈。预防指防止潜在疾病和/或防止症状恶化或疾病发展。
如本文所用，“疗效”表示由个体的治疗所导致的效果，其改变、通常改良或改善疾病或疾病状况的症状，或者治愈疾病或疾病状况。
如本文所用，“治疗有效量”或“治疗有效剂量”指施用于对象之后至少足以产生疗效的物质、化合物、材料或包含化合物的组合物的量。因此，其为防止、治愈、改善、阻滞或部分阻滞疾病或病症的症状所必需的量。
如本文所用，“预防有效量”或“预防有效剂量”指在施用于对象时会具有预期的预防效果的物质、化合物、材料或包含化合物的组合物的量，例如，防止或延迟疾病或症状的发生或复发，减少疾病或症状发生或复发的可能性。完全预防有效剂量不必通过施用一个剂量发生，并且可以仅在施用一系列剂量之后发生。因此，预防有效量可以在一次或多次施用中施用。
如本文中所使用的，术语“患者”是指哺乳动物，例如人。
Holst(Holst,J.J.Physiol.Rev.2007,87,1409)和Meier(Meier,J.J.Nat.Rev.Endocrinol.2012,8,7 28)描述了GLP-1受体激动剂，如GLP-1、利拉鲁肽和毒蜥外泌肽-4。
本发明的某些化合物通常在宽剂量范围内有效。例如，每周一次给药的剂量可以在每人每周约0.05至约30mg的范围内。本发明的某些化合物可以每天给药。另外，本发明的某些化合物可以每周一次给药。
应当理解，根据所述实施方案的治疗剂将与药学上可接受的合适的载体、赋形剂、以及其它被掺入制剂中以提供改善的转移、递送、耐受性等的试剂一同施用。大量适当的制剂可见于所有药物化学工作者已知的药典中：Remington's Pharmaceutical Sciences(第15版，Mack Publishing Company,Easton,Pa.(1975))，特别是其中Blaug、Seymour的第87章。这些制剂包括例如粉末、糊剂、膏剂、凝胶剂、蜡、油、脂质、含脂质(阳离子或阴离子)载体(例如LipofectinTM)、DNA缀合物、无水吸浆、水包油和油包水乳液、乳液聚乙二醇(各种分子量的聚乙二醇)、半固态凝胶以及含有聚乙二醇的半固态混合物。任何前述混合物均可适用于根据本发明的治疗或疗法，条件是制剂中的活性成分不被制剂灭活并且制剂在生理学上是相容的并耐受给药途径。
如本文所用，术语“药学上可接受的载体”旨在包括与药物给药相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延缓剂等。合适载体描述于最新版的 Remington's Pharmaceutical Sciences中，这是本领域的标准参考书目，其以引用方式并入本文。此类载体或稀释剂的优选示例包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和5％的人血清白蛋白。也可以使用脂质体和非水性载体，例如固定化油。将此类介质和试剂用于药物活性物质是本领域熟知的。
待用于临床体内施用的制剂必须为无菌的。这可容易地通过无菌滤膜过滤实现。
本发明的化合物可以与多种无机酸或有机酸中的任意反应形成药学上可接受的酸加成盐。药学上可接受的盐和制备它们的常用方法是本领域公知的。参见例如Handbook of Pharmaceutical Salts:Properties,Selection and Use.第二修订版(Wiley-VCH,2011)；S.M.Berge等人“Pharmaceutical Salts”,Journal of Pharmaceutical Sciences,Vol.66,No.1,1977年1月。常用的药学上可接受的盐包括三氟乙酸盐、磷酸盐、醋酸盐、柠檬酸盐、盐酸盐等。
本发明的化合物可以与多种无机碱或有机碱中的任意反应形成药学上可接受的盐，常用的药学上可接受的盐包括钠盐、钾盐、铵盐等。
将所述实施方案的药物组合物配制成与其预期施用途径相容。给药途径的示例包括肠胃外，例如静脉内、皮内、皮下、经口(例如吸入)、经皮(即局部的)、经粘膜和直肠给药。用于肠胃外、皮内或皮下施用的溶液或悬浮液可包括以下组分：注射用无菌稀释剂例如水、盐溶液、固定油、聚乙二醇类、甘油、丙二醇或其它合成溶剂；抗细菌剂，例如苄醇、对羟基苯甲酸甲酯、苯酚或间甲酚；抗氧化剂，例如抗坏血酸或亚硫酸氢钠；螯合剂，例如乙二胺四乙酸(EDTA)；缓冲剂，例如乙酸盐、柠檬酸盐或磷酸盐、以及调节渗透压的试剂，例如氯化钠或右旋糖。pH可用酸或碱进行调节，例如盐酸或氢氧化钠。可将肠胃外制剂包装在安瓿瓶、西林瓶、一次性注射器、玻璃或塑料制多剂量小瓶或注射笔内。注射笔主要有两种类型，一种是一次性的预填充式笔，内装有药物，无需更换药物笔芯，用完后即可扔掉；另一种是更为常用的耐用型注射笔，由注射笔和药物笔芯构成，用完后更换笔芯即可继续使用。
适于注射用途的药物组合物包括无菌水性溶液(在此是水溶性的)或分散体以及用于即时制备无菌注射液或分散体的无菌粉末。对于静脉内施用，合适的载体包括生理盐水、抑菌水、Cremophor ELTM(BASF，Parsippany,N.J.)或磷酸盐缓冲盐水(PBS)。在所有情况下，组合物必须是无菌的并且流动性应当达到易于注射的程度。其在制造和储存条件下必须是稳定的并且必须能防止微生物例如细菌和真菌的污染作用。载体可以是含有例如水、乙醇、多元醇(例如，甘油、丙二醇和液体聚乙二醇等)的溶剂或分散介质，及其适宜的混合物。例如通过利用涂层例如卵磷脂，在分散体情况下维持所需颗粒尺寸，以及利用表面活性剂，可以保持适宜的流动性。对微生物作用的防止可以通过各种抗细菌剂和抗真菌剂例如对羟基苯甲酸酯、氯代丁醇、苯酚、间甲酚、抗坏血酸、硫柳汞等来实现。在许多情况下，将优选在组合物中包含等渗剂，例如糖、多元醇(诸如甘露糖醇、山梨醇)、氯化钠。注射用组合物的延长吸收可通过在所述组合物中包含延缓吸收的试剂例如单硬脂酸铝和明胶来达到。
根据需要，可以通过将本发明化合物以所需量掺入具有上文所列成分中的一种或组合(按需要)的合适溶剂中来制备无菌注射溶液，然后过滤消毒。一般来讲，通过将本发明化合物掺入含有分散介质和上文所列那些所需其它成分的无菌载体中来制备分散体。就用于制备无菌注射溶液的无菌粉末而言，制备方法是获得粉末的真空干燥和冷冻干燥，该粉末包含活性成分和任何另外的期望成分，它们来自前述的这些成分的无菌过滤溶液。
对于吸入给药，从包含合适推进剂如二氧化碳等气体的加压容器或分配器或者喷雾器以气溶胶喷雾形式递送化合物。
还可以通过经粘膜或透皮方式全身给药。对于经粘膜或透皮给药，在制剂中使用适于渗透屏障的渗透剂。此类渗透剂通常在本领域是通常所知的，并且包括如用于经粘膜给药的去污剂、胆盐和夫西地酸衍生物。经粘膜给药可以通过使用喷鼻剂或栓剂来实现。对于透皮给药，可将一种或多种所述本发明化合物配制成如本领域通常所知的膏剂、软膏、凝胶、或霜膏。
还可将化合物以栓剂(例如，具有常规栓剂基质，如可可脂或其它甘油酯)或滞留性灌肠剂形式进行制备以用于经直肠递送。
在一个实施方案中，所述本发明化合物可用防止其被身体迅速消除的载体制备，例如缓释/控释制剂，包括植入体和微胶囊化递送体系。可使用可生物降解、可生物相容的聚合物，例如乙烯-乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备此类制剂的方法对于本领域技术人员而言是显而易见的。
例如，这些活性成分可胶囊包封于例如通过凝聚技术或通过界面聚合法制备的微胶囊中，例如分别在胶体给药系统(例如，脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊剂)或大乳液中的羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊。
可制备缓释制剂。适宜的缓释制剂的示例包括含有本发明化合物的固体疏水聚合物的半透性基质，该基质是成型制品形式例如膜或微胶囊。缓释基质的示例包括聚脂、水凝胶(例如，聚(2-羟乙基-甲基丙酸酯)、或聚(乙烯醇))、聚交酯(美国专利No.3,773,919)、L-谷氨酸和γ乙基-L-谷氨酸盐的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解乳酸-乙醇酸共聚物例如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的注射用微球)、和聚-D-(-)-3-羟基丁酸。虽然聚合物例如乙烯-乙酸乙烯酯和乳酸-乙醇酸能够释放分子100天以上，但是一些水凝胶释放蛋白质的时间却较短。聚乳酸(PLA)和聚乳酸乙醇酸共聚物(PLGA)是近年来研究的热点。此外，还有清蛋白微球、壳聚糖微球、明胶微球等。
脂质体混悬剂也可以用作药学上可接受的载体。这些可根据本领域技术人员已知的方法制备，例如在美国专利No.4,522,811中有所描述。
尤其有利的是以剂量单位形式配制肠胃外组合物以易于施用和剂量的一致性。如本文所用，剂量单位形式是指用于待治疗的受试者，适合作为单位剂量的物理上可分离的单位；每个单位含有经计算与所需药物载体结合产生期望治疗效果的预定量的一种或多种所述本发明化合物。所述实施方案的剂量单位形式的规格由以下指示并直接取决于：本发明化合物的独特特征和待实现的具体治疗效果，和用于治疗个体的此类本发明化合物的调配领域中固有的局限性。
所述药物组合物可与给药说明书一起放于容器、包装、或分配器中。
本发明提供了一种用于治疗患者中2型糖尿病的方法，包括向需要这种治疗的患者施用有效量的本发明化合物或其药学上可接受的盐。本发明还提供了一种用于治疗患者中2型糖尿病的方法，包括向需要这种治疗的患者施用有效量的本发明化合物或其药学上可接受的盐，其中所述施用是皮下的。本发明还提供了一种治疗患者中2型糖尿病的方法，包括向需要这种治疗的患者施用有效量的本发明化合物或其药学上可接受的盐，以及同时、分开，或相继施用有效量的一种或多种其他活性成分。在一个实施方案中，其他一种或多种活性成分是目前可获得的降低葡萄糖的药物，所述药物来自在施用前被视为护理标准的药物(由诸如美国糖尿病协会(American Diabetes Association)的行业指南确定)。
本发明还提供了治疗或预防下列疾病或状况的方法：葡萄糖耐量受损(IGT)、高血糖症、1型糖尿病、2型糖尿病、肥胖症、代谢综合征和神经退行性疾病，特别是用于延缓或预防2型糖尿病中的疾病进展，延缓从葡萄糖耐量受损到2型糖尿病的进展；延缓从2型糖尿病到需要胰岛素的糖尿病的进展；治疗代谢综合征，用于调节食欲，诱发饱足感，减少食物摄入，增加能量消耗，治疗肥胖症或预防超重；预防减肥成功后的体重反弹；治疗与超重或肥胖症相关的疾病或状态；治疗贪食症；治疗暴食；治疗血脂异常、动脉粥样硬化、高血压、冠心病、β-阻断剂中毒；非酒精性脂肪性肝病(NAFLD,non-alcoholic fatty liver disease)(可分为单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化)；用于抑制胃肠道的运动，用于与使用如X射线、CT和NMR扫描的技术的胃肠道调查联用。所述方法包括向需要这种治疗的患者施用有效量的本发明化合物或其药学上可接受的盐或其溶剂化物，以及同时、分开，或相继施用有效量的一种或多种其他活性成分。
进一步优选的医药用途包括治疗或预防退行性疾病，特别是神经退行性疾病如阿兹海默病(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、亨廷顿氏舞蹈病(Huntington's disease)、共济失调(例如脊髓小脑性共济失调)、肯尼迪病(Kennedy disease)、肌强直性营养不良、路易体痴呆症(Lewy body dementia)、多系统萎缩(multi-systemic atrophy)、肌萎缩性脊髓侧索硬化、原发性脊髓侧索硬化、脊髓性肌萎缩、朊病毒相关疾病(例如克雅氏病(Creutzfeldt-Jacob disease))、 多发性硬化、毛细血管扩增、贝敦氏症(Batten disease)、皮层基底节变性(corticobasal degeneration)、脊髓亚急性联合变性、脊髓痨、泰-萨二氏病(Tay-Sachs disease)、中毒性脑病、婴儿雷夫叙姆病(infantile Refsum disease)、雷夫叙姆病、神经棘红细胞增多症、尼曼匹克症(Niemann-Pick disease)、莱姆病(Lyme disease)、马查多·约瑟夫病(Machado-Joseph disease)、桑德霍夫病(Sandhoff disease)、雪-杜二氏综合征(Shy-Drager syndrome)、刺猬摇摆综合征(wobbly hedgehog syndrome)、原发病(proteopathy)、脑β-淀粉样脑血管病、青光眼中的视网膜神经节细胞变性、核蛋白病(synucleinopathies)、滔蛋白病(tauopathies)、额颞叶变性(FTLD)、痴呆症、Cadasil综合征、具有淀粉样变性的遗传性脑溢血、亚历山大病(Alexander disease)、seipinopathies、家族性淀粉样变性神经病变、老年系统性淀粉样变性(senile systemic amyloidosis)、serpinopathies、AL(轻链)淀粉样变性(原发性全身淀粉样变性)、AH(重链)淀粉样变性、AA(继发性)淀粉样变性、主动脉内淀粉样变性(aortic medial amyloidosis)、ApoAI淀粉样变性、ApoAII淀粉样变性、ApoAIV淀粉样变性、芬兰型家族性淀粉样变性(FAF)、溶菌酶淀粉样变性、纤维蛋白原淀粉样变性、透析淀粉样变性、包涵体肌炎/肌病、白内障、具有视紫红质突变的视网膜色素变性、甲状腺髓样癌、心脏心房淀粉样变性、垂体催乳素瘤、遗传性网格状角膜营养不良(Hereditary lattice corneal dystrophy)、皮肤性苔藓状淀粉样变性、马洛里小体(Mallory bodies)、角膜乳铁蛋白淀粉样变性、肺泡蛋白沉着症(pulmonary alveolar proteinosis)、牙原性(Pindborg)肿瘤淀粉体、囊性纤维化病、镰状细胞疾病或危重病性肌病(CIM)。进一步的医药用途包括治疗骨骼相关的病症，如骨质疏松症或骨关节炎等，其中骨形成的增加和骨吸收(bone resorption)的减少可能是有益的。
缩略语
保护基：
Aloc或AOC,allyloxycarbonyl:烯丙氧羰基；Bom,benzyloxymethyl:苄氧甲基；2-Br-Z,2-bromobenzyloxycarbonyl:2-溴苄氧羰基；tBu,t-butyl:叔丁基；Bz,benzoyl:苯甲酰基；Bzl,benzyl:苄基；Boc,tert-butoxycarbonyl:叔丁氧羰基；CHO,formyl:甲酰基；cHx,cyclohexyl:环己基；Cbz或Z,benzyloxycarbonyl:苄氧羰基；2-Cl-Z,2-chlorobenzyloxycarbonyl:2-氯苄氧羰基；Fm,9-fluorenylmethyl:9-芴基甲基；Fmoc,9-fluorenylmethoxycarbonyl:9-芴甲氧羰基；Mtt,4-methyltrityl:4-甲基三苯甲基；Pmc,(2,2,5,7,8-pentamethylchroman-6-sulphonyl:2,2,5,7,8-五甲基-6-羟基色满；Tos,4-toluenesulphonyl:对甲苯磺酰；Trt,triphenylmethyl:三苯甲基；Xan,xanthyl:吨基、氧(杂)蒽基。
试剂和溶剂：
ACN,acetonitrile：乙腈；BOP,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate:苯并三唑-1-三(三甲氨基)-六氟磷酸酯(卡特缩合剂)；DCC,N,N'-Dicyclohexylcarbodiimide:二环己基碳化二亚胺；DCM:二氯甲烷；DEPBT,3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one:3-(二乙氧基邻酰氧基)-1,2,3-苯并三嗪-4-酮；DIC,N,N'-Diisopropylcarbodiimide:N,N'-二异丙基碳二亚胺；DIPEA(或DIEA)，diisopropylethylamine：二异丙基乙胺；DMF：N,N-二甲基甲酰胺；DMSO：二甲亚砜；EDC或EDCI,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；EtOAc:乙酸乙酯；HATU，1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate：1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐；HBTU，O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；HOAT，1-Hydroxy-7-azabenzotriazole：1-羟基-7-氮杂苯并三唑；HOBT,1-hydroxybenzotriazole:1-羟基-苯并-三氮唑；Cl-HOBT：6-氯-1-羟基-苯并-三氮唑；NMM,N-Methylmorpholine:N-甲基吗啉；NMP,N-methylpyrrolidinone：N-甲基吡咯烷酮；Su，succinimide:琥珀酰亚胺；TBTU，2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate：O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯；TEA,triethylamine:三乙胺；TFA,trifluoroacetic acid三氟乙酸；TIS，triisopropylsilane：三异丙基硅烷；TMP，2,2,6,6-Tetramethylpiperidine：2.2.6.6-四甲基哌啶。
多肽化学合成方法
多肽固相化学合成方法是一种发展完善的方法学，可参文献例如R.C.Sheppard,Solid Phase Peptide Synthesis.A Practical Approach,Oxford-IRL Press,New York,1989。
线性多肽使用Boc固相多肽合成法或Fmoc固相多肽合成法。如果使用Fmoc化学合成C-末端是羧基的多肽，通常选用Wang树脂；C-末端是酰胺的多肽通常选用Rink amide树脂(包括Rink Amide-AM树脂、Rink Amide-MBHA树脂等同类树脂)。如果使用Boc化学合成C-末端是羧基的多肽，通常选用Pam树脂；C-末端是酰胺的多肽通常选用MBHA树脂。常用的缩合剂和活化剂是DIC和HOBT，其他可选肽键缩合剂包括EDC、BOP、HBTU、DEPBT、TBTU等。根据反应难度，氨基酸可以用1.1倍-10倍当量，反应时间15分钟-24小时。多肽可以手工合成，也可以使用多肽固相合成仪合成。
Fmoc保护基用20％哌啶/DMF脱除。Boc保护基用TFA脱除。肽键缩合反应用茚三酮(Ninhydrin，2,2-Dihydroxyindane-1,3-dione)试剂监测。
固相合成可以选用已预装载C末端氨基酸的树脂，或者选用未装载氨基酸的树脂。
在Rink Amide树脂上装载第一个氨基酸的方法可参考业内通常做法。一种常用方法简述如下：称量适量的树脂，在固相合成管中用20％哌啶/DMF脱除Fmoc保护基(15mL/g树脂，30分钟X2)，用DMF洗涤树脂。称量相当于树脂氨基5倍当量的Fmoc氨基酸、HATU、HOAT和10倍当量的NMM，加入DMF混匀后转入固相合成管。反应过夜后，用DMF洗涤树脂。向固相合成管加入1:1醋酸酐/吡啶(v/v)，30分钟后排空，用DMF洗涤树脂。第一个氨基酸装载完毕。
使用Fmoc固相多肽合成法时，常用的氨基酸及保护基如下：
Fmoc-Cys(Trt)-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-His(Trt)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Asn(Trt)-OH、Fmoc-Gln(Trt)-OH、Fmoc-Arg(Pmc)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH
合成过程中采用有适当保护的结构单元，如上述标准氨基酸、Fmoc-8-氨基-3,6-二氧杂辛酸(CAS No.166108-71-0)、Fmoc-Glu-OtBu(CAS No.84793-07-7)。脂肪酸部分的引入可以使用结构单元来实现，例如但不限于二十烷二酸单叔丁酯。在每个偶联步骤之后，未反应的肽中间体可以用乙酸酐(10当量)和过量可力丁(20当量)封端。
固相Fmoc化学合成多肽后，常用的切割试剂是TFA。将干树脂放在一个摇瓶中，加入适当量含有90:4:2:2:2(v/v)三氟乙酸：三异丙基硅烷：1,2-乙二硫醇：水：苯甲硫醚切割液(10-25mL/g树脂)，盖上盖子，在室温下进行间歇式旋转震荡。2小时后抽滤树脂，以新的TFA清洗树脂2-3次，合并滤液，滴加8-10倍体积的冰乙醚。最后，离心收集沉淀出来的多肽粗品。
使用Boc固相多肽合成法时，常用氨基酸和保护基如下：
Boc-Cys(4-MeBzl)-OH、Boc-Asp(OcHx)-OH、Boc-Glu(OcHx)-OH、Boc-His(Bom)-OH、Boc-Lys(2-Cl-Z)-OH、Boc-Asn(Xan)-OH、Boc-Arg(Tos)-OH、Boc-Ser(Bzl)-OH、Boc-Thr(Bzl)-OH、Boc-Trp(CHO)-OH和Boc-Tyr(2-Br-Z)-OH
如果赖氨酸的侧链氨基用于合成内酰胺或酰化反应，赖氨酸的侧链氨基可以使用烯丙氧羰基(aloc)保护或Fmoc保护。如果天冬氨酸或谷氨酸的侧链羧基用于内酰胺合成或酰化反应，羧基应该转化为烯丙酯或9-芴基甲基保护，例如Boc-Glu(OAllyl)-OH、Boc-Glu(Ofm)-OH。
固相Boc化学合成多肽后，对于PAM、MBHA树脂，通常采用HF切割，每0.1毫摩尔树脂加5毫升HF，同时加入对甲苯酚、对巯基苯酚或苯甲醚等试剂，混合物在冰浴条件下搅拌1小时。真空抽干HF后，多肽用冰乙醚沉淀，离心收集沉淀，经过HPLC分离纯化，冷冻干燥得到最后产品。
纯化
将粗肽溶于水和乙腈(例如水/乙腈(3:1))的合适混合物中，并通过反相制备型HPLC(例如AKTA purifier、岛津LC-20AR等)纯化，根据装载的粗肽量和极性大小选用不同填料和大小的柱子，例如C8或C18半制备柱或制备柱。缓冲液A为0.1％TFA水溶液，缓冲液B为0.1％TFA,100％乙腈。缓冲液B梯度上升进行洗脱。相关级分(fraction)通过分析型HPLC检 查,使用ZORBAX 300SB-C18(4.6X250mm,5μM)柱，缓冲液A为0.1％TFA水溶液，缓冲液B为0.1％TFA，100％乙腈。流速1ml/min，在210nm波长检测。将含有纯度合格的目标肽的级分混合并冷冻干燥，得到多肽为白色固体。产品分装于玻璃小瓶中保存。
制备方法(1)
本发明的化合物是直链肽。可以按照多肽序列自C末端至N末端的顺序逐步偶联每一个氨基酸，从而得到多肽主链。过程为：首先将一个氨基被封闭基团保护的氨基酸共价连接在固相载体上，脱掉第一个氨基酸的氨基保护基，这样第一个氨基酸就接到固相载体上。然后氨基被封闭的第二个氨基酸的羧基经过活化后，与己接在固相载体的第一个氨基酸的氨基反应形成肽键，这样在固相载体上就生成了一个带有保护基的二肽。重复上述肽键形成反应，使肽链从C端向N端延长，直至生成所需要的肽链。最后将多肽与树脂切割分离，经过纯化、冻干，得到多肽产品。
本发明部分化合物通过侧链含有氨基或者巯基的氨基酸的侧链氨基或者巯基缀合长效基团或者修饰基团。以化合物12为例说明合成路线和方法。
化合物12的合成包括如下步骤：
步骤A：将Fmoc-Lys(PG)-OH和树脂偶联得到Fmoc-Lys(PG)-树脂，PG为赖氨酸侧链氨基的保护基团；
步骤B：Fmoc-Lys(PG)-树脂经第一逐步偶联氨基酸或氨基酸衍生物，得到序列如化合物12主肽链所示的第一肽树脂；
步骤C：脱除序列如化合物12主肽链所示的第一肽树脂中主肽链C末端Lys的侧链保护基团PG，经第二逐步偶联2-(2-(2-氨乙氧基)乙氧基)乙酸、2-(2-(2-氨乙氧基)乙氧基)乙酸、γ-Glu和二十烷二酸，获得第二肽树脂；
步骤D：取第二肽树脂经裂解、纯化和冻干，得到化合物12。
优选地，步骤A中树脂可以选用Rink Amide树脂(包括Rink Amide-AM树脂、Rink Amide-MBHA树脂等同类树脂)。优选地，Lys的侧链保护基为aloc、Mmt、Mtt、Dde或者ivDde。
优选地，偶联采用的试剂选自DIC+A、B+A+C或B+C，其中A选自HOAt或HOBt，B选自EDC、HATU、BOP、PyBOP、PyAOP、HBTU、TBTU或DEPBT，C选自DIPEA、TEA、NMM或TMP。
例如，步骤B中第一逐步偶联和步骤C中第二逐步偶联采用的偶联剂包括缩合剂和反应溶剂，缩合剂可以是DIC和HOBt的混合液，PyBOP、HOBt和DIEA的混合液，或HATU、HOAt和DIEA的混合液，或DEPBT和DIEA的混合液，或HBTU和DIEA的混合液。反应溶剂为DMF、DCM、NMP或DMSO中的一种、两种或两者以上的混合液。
步骤B中第一逐步偶联时，根据化合物12序列，逐步偶联Fmoc-Pro-OH、Fmoc-Pro-OH、Fmoc-Pro-OH、Fmoc-Ala-OH、Fmoc-Gly-OH、Fmoc-Ser(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Pro-OH、Fmoc-Gly-OH、Fmoc-Gly-OH、Fmoc-Ala-OH、Fmoc-Leu-OH、Fmoc-Leu-OH、Fmoc-Trp(Boc)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Ile–OH、Fmoc-Phe-OH、Fmoc-Leu-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Val-OH、Fmoc-Ala-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Leu-OH、Fmoc-Ala-OH、Fmoc-Ile–OH、Fmoc-Ser(tBu)-OH、Fmoc-Leu-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Phe-OH、Fmoc-Thr(tBu)-OH、Fmoc-Gly-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Aib-OH和Boc-Tyr(tBu)-OH。
当PG是aloc时，步骤C中脱除保护基采用的试剂为1-20当量吗啡啉(或者1-20当量的苯硅烷替代吗啡啉)与0.05-3当量Pd(PPh 3) 4。优选地，aloc保护基用5-10当量吗啡啉(或者5-10当量的苯硅烷替代吗啡啉)与0.1-0.3当量Pd(PPh 3) 4脱除。保护基脱除反应可以进行两次，每次10-30分钟，优先选用CH 2Cl 2为溶剂。
脱除Aloc保护基的另一个方法是用催化量的四(三苯基膦)钯(0)和37:2:1比例的DCM、冰醋酸和NMM(15mL/g树脂)在氩气环境、室温条件下搅拌2小时。反应后每克树脂用0.5％ DIPEA/DMF(10mL)，0.5％二乙基二硫代氨基甲酸钠/DMF(3X 10mL)，1:1DCM:DMF(5X10mL)清洗。
当PG是Dde或ivDde时，步骤C中脱除保护基采用的试剂为水合肼/DMF混合液。配制2％(w/v)水合肼的DMF溶液(25mL/g树脂)，加入树脂，5分钟后抽干，用DMF洗树脂。用2％水合肼/DMF脱保护基及DMF洗涤的过程重复3次。
当PG是Mmt或Mtt时，步骤C中脱除保护基采用的试剂为1-2％TFA/DCM混合液。
步骤C中第二逐步偶联时，根据化合物12序列，逐步偶联Fmoc-8-氨基-3,6-二氧杂辛酸(CAS No.166108-71-0)、Fmoc-8-氨基-3,6-二氧杂辛酸、Fmoc-Glu-OtBu(CAS No.84793-07-7)和二十烷二酸单叔丁酯HOOC-(CH2) 18-COOtBu。步骤D中裂解采用的试剂包括TFA及PhSMe、PhOMe、EDT、H 2O、TIS、PhOH中的一种、两种或者两种以上的混合物。例如，裂解采用的试剂为TFA、苯甲硫醚、甲硫醚和EDT的混合液，TFA、苯甲硫醚、甲硫醚和EDT的体积比为90:5:3:2。优选地，裂解采用的试剂为TFA、H 2O和TIS混合液，体积比为95:2.5:2.5。
制备方法(2)
本发明部分化合物通过侧链含有氨基或者巯基的氨基酸的侧链氨基或者巯基缀合长效基团或者修饰基团。化合物可以按照多肽序列自C末端向N末端的顺序逐步偶联每一个氨基酸，直至偶连上侧链需要缀合长效基团或修饰基团的氨基酸残基X。在不影响氨基酸残基X的α-氨基的保护基的前提下，脱除氨基酸残基X的侧链保护基，完成长效基团或修饰基团的合成。然后脱除氨基酸残基X的α-氨基的保护基，顺序逐步偶联多肽主链剩余的每一个氨基酸，从而得到完整多肽。最后将多肽与树脂切割分离，经过纯化、冻干，得到多肽产品。
以化合物12为例说明合成路线和方法。化合物12的合成包括如下步骤：
步骤A：将PG1-Lys(PG2)-OH和树脂偶联得到PG1-Lys(PG2)-树脂，PG1为赖氨酸α-氨基的保护基团，PG2为赖氨酸侧链氨基的保护基团；
步骤B：脱除PG1-Lys(PG2)-树脂中该赖氨酸的侧链保护基团PG2，经第二逐步偶联2-(2-(2-氨乙氧基)乙氧基)乙酸、2-(2-(2-氨乙氧基)乙氧基)乙酸、γ-Glu和二十烷二酸，获得第三肽树脂；
步骤C：脱除该赖氨酸α-氨基的保护基团PG1，经第一逐步偶联氨基酸或氨基酸衍生物，得到序列如化合物12所示的第四肽树脂；
步骤D：取第四肽树脂经裂解、纯化和冻干，得到化合物12。
优选地，步骤A中树脂可以选用Rink Amide树脂(包括Rink Amide-AM树脂、Rink Amide-MBHA树脂等同类树脂)。
优选地，Lys的侧链保护基团PG2为Fmoc、aloc、Mmt、Mtt、Dde或者ivDde。Lys的α-氨基的保护基团PG1为aloc、Mmt、Mtt、Dde或者ivDde。PG1和PG2必须是正交的。用于化合物12合成的PG1-Lys(PG2)-OH的例子包括Dde-Lys(Fmoc)-OH、Alloc-Lys(Fmoc)-OH等。保护基团的脱除方法参考制备方法(1)、实施例或多肽固相合成的文献。
优选地，偶联采用的试剂选自DIC+A、B+A+C或B+C，其中A选自HOAt或HOBt，B选自EDC、HATU、BOP、PyBOP、PyAOP、HBTU、TBTU或DEPBT，C选自DIPEA、TEA、NMM或TMP。
步骤B中第二逐步偶联时，根据化合物12序列，逐步偶联Fmoc-8-氨基-3,6-二氧杂辛酸(CAS No.166108-71-0)、Fmoc-8-氨基-3,6-二氧杂辛酸、Fmoc-Glu-OtBu(CAS No.84793-07-7)和二十烷二酸单叔丁酯HOOC-(CH2) 18-COOtBu。
步骤C中第一逐步偶联时，根据化合物12序列，逐步偶联Fmoc-Pro-OH、Fmoc-Pro-OH、Fmoc-Pro-OH、Fmoc-Ala-OH、Fmoc-Gly-OH、Fmoc-Ser(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Pro-OH、Fmoc-Gly-OH、Fmoc-Gly-OH、Fmoc-Ala-OH、Fmoc-Leu-OH、Fmoc-Leu-OH、Fmoc-Trp(Boc)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Ile–OH、Fmoc-Phe-OH、Fmoc-Leu-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Val-OH、Fmoc-Ala-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Leu-OH、Fmoc-Ala-OH、Fmoc-Ile–OH、Fmoc-Ser(tBu)-OH、 Fmoc-Leu-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Phe-OH、Fmoc-Thr(tBu)-OH、Fmoc-Gly-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Aib-OH和Boc-Tyr(tBu)-OH。
优选地，步骤D中裂解方法与采用的试剂与制备方法(1)相同。
本发明还包括可用于合成本发明化合物或其药学上可接受盐的新的中间体和方法。本发明的中间体和化合物可以通过本领域已知的多种方法制备。特别地，在下面的实施例中举例说明了使用化学合成的方法。所描述的每一途径的具体合成步骤可以以不同的方式组合，以制备本发明的化合物或其盐。试剂和原料是本领域普通技术人员容易获得的。
实施例
参照实施例进一步阐释本发明。这些实施例绝非旨在限制所请求保护的本发明的范围。本领域技术人员可以借鉴本发明的内容，适当改进工艺参数，对本发明所述方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。所有类似的替换和改动对本领域技术人员是显而易见的，它们都被视为包括在本发明中。
氨基酸原料、缩合试剂等购自吉尔生化(上海)有限公司。Rink Amide树脂购自上虞普尔公司和天津南开和成科技有限公司。
实施例1化合物58的合成
选取预装载的Fmoc-Ser(tBu)-Rink Amide树脂，用20％哌啶/DMF脱除Fmoc保护基(2X10分钟)，用DMF洗涤树脂3遍。使用Fmoc固相多肽合成法。将氨基酸(相对于树脂氨基酸载量10当量)溶于DMF，再加入HOBT和DIC(相对于树脂氨基酸载量10当量)，混匀后加入树脂，在室温偶联120分钟。排空固相反应管中的溶液，用DMF洗涤树脂3遍。至此完成一个合成单元的偶联。多肽自C末端至N末端的每个合成单元都采用同样的偶联方法，氨基酸残基使用“多肽固相化学合成方法”部分及制备方法部分列举的Fmoc固相合成常用的保护基或其它适合本序列的保护基。主肽链N末端的酪氨酸使用Boc-Tyr(tBu)-OH。从N末端数第24个氨基酸Lys24使用Fmoc-Lys(Dde)-OH。
主肽链合成后，Lys24侧链Dde保护基用2％水合肼/DMF脱除。配制2％(w/v)水合肼的DMF溶液(25mL/g树脂)，加入树脂，10分钟后抽干，用DMF洗树脂。用2％水合肼/DMF脱保护基及DMF洗涤的过程重复3次。
Lys24侧链取代基的合成使用结构单元Fmoc-8-氨基-3,6-二氧杂辛酸(CAS No.166108-71-0)、Fmoc-Glu-OtBu(CAS No.84793-07-7)和二十烷二酸单叔丁酯HOOC-(CH 2) 18-COOtBu。侧链取代基每个结构单元的用量是树脂氨基酸载量10当量，每步偶联时间为4小时。
肽链合成后树脂用DCM洗涤，加入含有90:4:2:2:2(v/v)三氟乙酸：三异丙基硅烷：1,2-乙二硫醇：水：苯甲硫醚切割液(10-25mL/g树脂)，在室温震荡2小时，用冰乙醚沉淀。粗肽溶于0.1％TFA，30％乙腈的水溶液，通过半制备或制备型RP-HPLC，使用例如Luna C1830X250mm，5μM反相柱。缓冲液A为0.1％TFA水溶液，缓冲液B为0.1％TFA,100％乙腈。缓冲液B梯度逐步上升进行洗脱，合并正确的级分(fraction)并低温冷冻干燥，得到白色固体。通过质谱分析和氨基酸测序确定多肽的结构。本发明中C末端是丝氨酸的化合物都可以按照实施例1的方法合成。
实施例2化合物15的合成
选取预装载的Fmoc-Lys(Aloc)-Rink Amide树脂(例如0.29mmole/g)。多肽自C末端至N末端的每个合成单元都采用实施例1的偶联方法，除C末端赖氨酸及N末端Boc-Tyr(tBu)-OH以外的氨基酸残基使用“多肽固相化学合成方法”部分及制备方法部分列举的Fmoc固相合成常用的保护基或其它适合本序列的保护基。主肽链合成后，脱除C末端赖氨酸侧链烯丙氧羰基可以用四(三苯基膦)钯(0)和37:2:1比例的DCM、冰醋酸和NMM(15mL/g树脂)在氩气环境、室温条件下搅拌2小时。四(三苯基膦)钯(0)可以使用催化量至1当量。反应后每克树脂用0.5％DIPEA/DMF(10mL)，0.5％二乙基二硫代氨基甲酸钠/DMF(3 X 10mL)，1:1DCM:DMF(5 X 10mL)清洗。Aloc保护基也可以用5-10当量吗啡啉(或者5-10当量的苯硅烷)与0.1-0.3当量 Pd(PPh 3) 4脱除。保护基脱除反应可以进行两次，每次30分钟，选用CH 2Cl 2为溶剂。脱除侧链Aloc保护基后，此赖氨酸侧链取代基的合成方法和步骤参考实施例1。
另外一种方法是选取预装载的Fmoc-Lys(ivDde)-Rink Amide树脂。主肽链的合成方法与上一段使用Fmoc-Lys(Aloc)-Rink Amide树脂的方法相同。主肽链合成后，C末端赖氨酸侧链ivDde保护基用2％水合肼/DMF脱除。配制2％(w/v)水合肼的DMF溶液(25mL/g树脂)，加入树脂，10分钟后抽干，用DMF洗树脂。用2％水合肼/DMF脱保护基及DMF洗涤的过程重复3次。此赖氨酸侧链取代基的合成方法和步骤与实施例1类似。
当PG是Mmt或Mtt时，步骤C中脱除保护基采用的试剂为1-2％TFA/DCM混合液。
本发明中C末端是赖氨酸而且侧链氨基连接长效基团的化合物可以用实施例2的方法合成，也可以采用“制备方法”部分化合物12的合成路线和方法。
实施例3化合物11合成
选取预装载的Fmoc-Cys(Trt)-Rink Amide树脂。其余合成方法和步骤与实施例1类似。本发明中C末端是半胱氨酸的化合物都可以按照实施例3的方法合成。
实施例4化合物65合成
选取预装载的Fmoc-Ala-Rink Amide树脂。其余合成方法和步骤与实施例1类似。本发明中C末端是丙氨酸的化合物都可以按照实施例4的方法合成。
实施例5化合物279合成
选取预装载的Fmoc-Gly-Rink Amide树脂。其余合成方法和步骤与实施例1类似。本发明中C末端是甘氨酸的化合物都可以按照实施例5的方法合成。
实施例6化合物356合成
选取预装载的Fmoc-Pro-Rink Amide树脂。其余合成方法和步骤与实施例1类似。本发明中C末端是脯氨酸的化合物都可以按照实施例6的方法合成。
表一列出了本发明中部分化合物的计算分子量和实测分子量。
表一
化合物 计算分子量 实测分子量 化合物 计算分子量 实测分子量
化合物1 5077.8 5077.6 化合物2 4990.7 4989.6
化合物3 5076.8 5076.7 化合物4 4989.8 4988.6
化合物5 4963.6 4962.5 化合物6 4948.7 4947.8
化合物7 5038.8 5037.9 化合物8 5020.8 5019.6
化合物9 4933.7 4933.0 化合物10 4940.8 4939.7
化合物11 4951.8 4950.7 化合物12 4876.7 4875.9
化合物13 4963.8 4962.5 化合物14 4977.8 4977.1
化合物15 4890.7 4889.8 化合物16 4891.7 4890.8
化合物17 4905.7 4905.6 化合物18 4557.3 4556.4
化合物19 4429.1 4428.4 化合物20 4642.4 4642.2
化合物21 4850.6 4850.3 化合物22 4866.6 4865.9
化合物23 4913.7 4913.5 化合物24 4836.6 4835.7
化合物26 4942.7 4942.2 化合物27 4822.5 4822.3
化合物28 4865.6 4864.7 化合物29 4879.6 4879.0
化合物30 4907.6 4906.9 化合物32 4865.6 4864.6
化合物33 4444.1 4443.4 化合物35 4473.2 4472.5
化合物36 4301.0 4300.3 化合物38 4914.6 4914.4
化合物39 4879.6 4878.8 化合物40 4835.6 4835.2
化合物41 4892.6 4891.9 化合物43 4443.1 4442.4
化合物44 4834.6 4834.5 化合物45 4819.6 4818.9
化合物46 4863.6 4862.7 化合物47 4899.6 4899.1
化合物48 4428.2 4427.4 化合物49 4807.6 4807.7
化合物53 4808.5 4807.9 化合物54 4793.5 4792.6
化合物55 4926.7 4926.3 化合物56 4834.6 4834.4
化合物57 4806.6 4806.1 化合物58 4849.7 4849.9
化合物59 4428.2 4427.6 化合物60 4300.0 4299.3
化合物61 4891.7 4891.1 化合物62 4848.7 4848.5
化合物63 4850.6 4850.4 化合物64 4822.5 4821.7
化合物65 4444.1 4443.7 化合物66 4864.6 4864.2
化合物67 4836.6 4836.8 化合物68 4458.1 4457.4
化合物71 4879.6 4879.0 化合物72 4914.6 4913.8
化合物73 4892.7 4891.9 化合物74 4864.6 4864.1
化合物76 4486.2 4485.4 化合物77 4358.1 4357.4
化合物78 4906.7 4906.5 化合物79 4878.6 4878.3
化合物80 4500.2 4499.8 化合物81 4372.1 4371.5
化合物82 4949.7 4949.3 化合物83 4984.8 4985.0
化合物126 4269.0 4268.6 化合物160 4431.2 4431.1
化合物207 4427.2 4427.5 化合物243 5038.8 5038.6
化合物279 4414.1 4414.4 化合物356 4610.4 4610.7
质谱分子量和氨基酸测序结果证明多肽结构正确。
多肽溶于生理盐水(pH 7.4)，制成原液(stock solution)。原液中多肽浓度通过Bradford法、紫外分光度检测法等常规方法定量。动物药效试验前根据给药量取含有所需剂量的多肽原液，用磷酸盐缓冲生理盐水(PBS，pH 7.4)稀释配成注射液。每只动物比较合适的注射液体积是5ml/kg体重。可以此计算需要配置的注射液的体积。
动物实验所有的数据将被录入到Excel文档中，并以mean±S.E.M的方式表示，多组间差异采用graphpad Prism 6软件比较采用单因素方差分析(One-way analysis of variance(ANOVA))Dunnett’s方法，两组间差异采用非配对T-Test方法，P值小于0.05时被认为有显著性差异。
实施例7
本发明的多肽体内药效可以在本领域已知的任何合适的动物模型中以及在临床试验中测定。例如db/db小鼠是一种比较合适的糖尿病动物模型。
db/db小鼠饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在40～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由一个电子定时开灯系统来控制，每天开灯12小时关灯12小时(上午7:00开，下午19:00关)。实验过程中，动物单笼饲养，并给每个笼中的小鼠提供玩具。实验过程中，动物自由饮水。db/db雄性小鼠(7周龄)适应试验环境一周。试验前三天
Figure PCTCN2021104805-appb-000094
记录基线血糖和体重。基于三日血糖和体重将小鼠随机分组，每组6只。小鼠皮下注射生理盐水(5ml/kg，对照组)或多肽化合物12和15(10nmol/kg)，在给药前0小时及给药后1、4、8、24、36和48小时采血，使用美国强生公司稳豪型血糖仪及配套试纸检测血糖。以时间为横坐标，不同时间点的血糖值为纵坐标，绘制血糖曲线，计算曲线下面积(AUC)，比较多肽化合物降血糖作用的时间和效果。
结果如图1所示。多肽化合物12和15均可以大幅度降低2型糖尿病小鼠的血糖，与对照组有统计学的显著差异。这两个化合物有潜力作为长效糖尿病治疗药物。
实施例8
本发明的多肽体内药效可以在本领域已知的任何合适的动物模型中测定。饮食诱导的肥胖(DIO)小鼠是肥胖症、胰岛素抵抗和高血脂常用动物模型。
5周龄雄性C57BL/6小鼠饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在30～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天上下午对温度和湿度各记录一次。动物饲养间的采光由一个电子定时开灯系统来控制，每天开灯12小时关灯12小时(上午6:00开，下午18:00关)。实验过程中，动物单笼饲养，并给每个笼中的小鼠提供玩具。动物从6周龄开始用高脂饲料饲养(各营养成分重量比为蛋白26.2％，碳水化合物26.3％，脂肪36.9％，提供热量百分比分别为20％、20％和60％)。饲养过程中，动物自由饮水。选取26周龄、平均体重50克左右雄性DIO小鼠进行试验。动物进行抓取适应、皮下注射适应1周。并在实验前连续3天称量体重和摄食量，实验前1天测量动物血糖，并按照动物的血糖与体重分组，每组8只。
实验期间，对照组每2天皮下注射一次PBS。利拉鲁肽组每2天皮下注射一次利拉鲁肽(60nmol/kg)。另外3组动物每2天皮下分别注射一次多肽55、58和243(20nmol/kg)，共给药11次。第23天称量动物的体重。体重变化百分比＝[(最终体重-起始体重)/起始体重]*100％。
结果如图2所示。多肽化合物55、58和243均可以降低2型糖尿病小鼠的体重，与对照组有统计学的显著差异，并且明显优于利拉鲁肽。这些化合物有潜力作为长效减肥药物。
实施例9药代动力学试验
SD大鼠每组8只，雌雄各半，8周龄，体重200-300g，研究本发明化合物单次皮下注射给药在大鼠体内的的药代动力学特征。化合物12、15和对照化合物(PCT/CN2020/070697中所述的肽化合物27)分别溶于PBS，制成1mg/mL溶液，按照75μg/kg剂量皮下注射，在0小时、0.5、2、4、8、12、24、48、72、96、120、144和168小时采集全血0.2ml后转入EDTA-K2抗凝管中，放入2-8℃离心机1200-1500×g离心10-15分钟，分离血浆至洁净管内，标记信息后置-60～-90℃冰箱保存。每个样品中多肽浓度使用LC-MS/MS方法检测，质谱仪为
Figure PCTCN2021104805-appb-000095
(Applied Biosystems/Sciex)，采用WinNonLin v 6.4(Pharsight Inc.)软件的非房室模型计算药代参数。化合物12的半衰期是9.82±0.49小时，化合物15的半衰期是10.46±0.71小时，对照化合物的半衰期是7.93±0.72小时。

Claims (13)

  1. 一种具有式(I)的肽化合物或其药学上可接受的盐或溶剂合物，
    Y-aib-E-G-T-F-T-S-D-X1-S-X11-X2-X12-E-X3-X4-A-X5-X6-X13-F-X7-X8-W-L-X9-X14-G-X10(I)
    其中，X1代表选自L、K、C或Y的氨基酸残基，或式(II)，或式(III)；X2代表选自Q、A、aib或Y的氨基酸残基；X3代表选自E、C或K的氨基酸残基，或式(II)，或式(III)；X4代表选自E、C或K的氨基酸残基，或式(II)，或式(III)；X5代表选自V或A的氨基酸残基，X6代表选自K、R、C或Q的氨基酸残基，或式(II)，或式(III)；X7代表选自I或V的氨基酸残基；X8代表选自E、Q、N、K、C或A的氨基酸残基，或式(II)，或式(III)；X9代表选自I、L、C或K的氨基酸残基，或式(II)，或式(III)；X10代表不存在或GPSSGAPPP，GPPSGAPPP，GPSSGKPPP，GPSSGEPPP，GPSSaibAPPP，GPSSGAPP，GPSSGAP，GPSSGA，GPSSG，GPSS，GPS，GP，G；X11代表I、C、S、K的氨基酸残基，或式(II)，或式(III)；X12代表L、C或K的氨基酸残基，或式(II)，或式(III)；X13代表L、E或D的氨基酸残基；X14代表选自A、C、K、R的氨基酸残基，或式(II)，或式(III)；所述式(II)或式(III)的结构如下：
    Figure PCTCN2021104805-appb-100001
    其中波浪线代表连接至相邻基团的连接点，n1为1-7的整数，
    任选地，式(II)含有侧链氨基的氨基酸残基在其侧链氨基被长效基团修饰，式(III)含有侧链巯基的氨基酸残基在其侧链巯基被长效基团修饰；优选地，式(II)是赖氨酸残基，式(III)是半胱氨酸残基，
    任选地，在X10的C端添加一个或两个选自S或者侧链含有氨基或者巯基的氨基酸，并且C末端氨基酸的羧基任选地被酰胺化为C末端酰胺，所述含有侧链氨基或者巯基的氨基酸残基具有式(II)或式(III)所示结构；当式(II)或式(III)为C末端氨基酸时，其羧基部分是COOH或CONH 2，优选地，式(II)是赖氨酸，式(III)是半胱氨酸，
    优选地，所述长效基团具有式(IV)的结构：
    O1-O2-O3-O4-O5-O6-O7-O8-(IV)，
    其中O1代表式(V)或(VI)的结构：
    Figure PCTCN2021104805-appb-100002
    其中n2为6-24的整数，优选10-24，进一步优选16-22；
    其中波浪线代表连接至相邻基团的氨基的连接点，O2-O3-O4-O5-O6-O7-O8-代表连接体，其中O2至O8中的每一个独立地由以下氨基酸残基或长链结构中的任一个表示：α-Glu、γ-Glu、α-Asp、β-Asp、α-hGlu、δ-hGlu、Gly、Ala、β-Ala、GABA或PEG2，或者O2至O8中的一个或多个不存在，条件是O2至O8中至少有两个存在，优选地，O2至O8中含有至少一个带负电荷的部分。
  2. 根据权利要求1的肽化合物或其药学上可接受的盐或溶剂合物，其中O2-O3-O4-O5-O6-O7-O8-代表选自下组的连接体：γGlu-PEG2-γGlu-、γGlu-PEG2-2×γGlu-、γGlu-PEG2-、γGlu-2×PEG2-、γGlu-3×PEG2-、γGlu-PEG2-γGlu-PEG2、γGlu-2×PEG2-γGlu-、γGlu-2×PEG2-2×γGlu-、2×γGlu-、2×γGlu-PEG2-、2×γGlu-PEG2-γGlu-、2×γGlu-PEG2-γGlu-PEG2-、2×γGlu-2×PEG2-、2×γGlu-2×PEG2-γGlu、2×γGlu-2×PEG2-2×γGlu-。
  3. 根据权利要求1或2的肽化合物或其药学上可接受的盐或溶剂合物，其中X10的C末端添加的含有侧链巯基的氨基酸在其侧链巯基被式(IV)的长效基团修饰，所述含有侧链巯基的氨基酸的侧链巯基通过迈克尔反应受体或硫醇反应性基团与连接基团L一端连接，优选地，所 述连接基团L另一端进一步通过氨基或羧基与式(IV)的长效基团形成共价键连接，优选地，所述连接基团L选自：-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NH-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-CO-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NHCO-(CH 2) n8-，-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NHCO-(CH 2) n8-NH-或其任意组合，其中n3、n4、n5、n6、n7、n8各自是0至10的整数，更优选地，L是-NH-CH 2-(CH 2CH 2O) 3-(CH 2) 3-NH-或-NH-(CH 2) n5-(CH 2CH 2O) n6-(CH 2) n7-NHCO-(CH 2) n8-。
  4. 根据前述权利要求任一项的肽化合物或其药学上可接受的盐或溶剂合物，其中赖氨酸侧链氨基缀合长效基团，该分子结构简称为K(x18)，具有式(VII)的结构：
    Figure PCTCN2021104805-appb-100003
    或者其中赖氨酸侧链氨基缀合长效基团，该分子结构简称为K(x20)，具有式(VIII)的结构
    Figure PCTCN2021104805-appb-100004
    其中波浪线代表连接至相邻氨基酸残基的连接点。
  5. 根据前述权利要求任一项的肽化合物或其药学上可接受的盐或溶剂合物，其中X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)；或者其中X1、X4、X8、X11、X12、X14中至少有一个是式(II)或式(III)；
    或者其中X1、X3、X4、X6、X8、X9、X11、X12、X14中至少有一个是式(II)或式(III)，且至少一个式(II)或式(III)侧链缀合长效基团或修饰基团。
  6. 根据前述权利要求任一项的肽化合物或其药学上可接受的盐或溶剂合物，其中所述肽化合物选自：
    Figure PCTCN2021104805-appb-100005
    Figure PCTCN2021104805-appb-100006
    Figure PCTCN2021104805-appb-100007
    Figure PCTCN2021104805-appb-100008
    Figure PCTCN2021104805-appb-100009
    Figure PCTCN2021104805-appb-100010
    Figure PCTCN2021104805-appb-100011
    Figure PCTCN2021104805-appb-100012
    Figure PCTCN2021104805-appb-100013
    Figure PCTCN2021104805-appb-100014
    Figure PCTCN2021104805-appb-100015
    Figure PCTCN2021104805-appb-100016
    化合物86.YaibEGTFTSDLSK(x20)ALEKEAVRLFIEWLIAGGPSSGA-NH 2
    化合物87.YaibEGTFTSDLSIQLEEEAVRLFIEWLIK(x20)GGPSSGAPPPS-NH 2
    化合物88.YaibEGTFTSDLSK(x18)ALEKEAVRLFIEWLKAGGPSS-NH2
    化合物89.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x18)-NH 2
    化合物90.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGA-NH 2
    化合物91.YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLIAGGPSS-NH2
    化合物92.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGK(x18)-NH 2
    化合物93.YaibEGTFTSDLSK(x20)QLEKEAVQDFVNWLLAGGPSSGAPPPS-NH 2
    化合物94.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH2
    化合物95.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x20)-NH 2
    化合物96.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGAPPPS-NH 2
    化合物97.YaibEGTFTSDLSK(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
    化合物98.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSK(x20)-NH 2
    化合物99.YaibEGTFTSDLSIaibK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物100.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSS-NH 2
    化合物101.YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物102.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x20)-NH 2
    化合物103.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x20)GGPSSGAPPPS-NH 2
    化合物104.YaibEGTFTSDLSIAC(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物105.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH 2
    化合物106.YaibEGTFTSDLSIQLEKEAVKLFVNWLIK(x20)GGPSSGAPPPS-NH 2
    化合物107.YaibEGTFTSDLSIAC(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物108.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSS-NH2
    化合物109.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC(x20)-NH 2
    化合物110.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
    化合物111.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGA-NH2
    化合物112.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH2
    化合物113.YaibEGTFTSDLSIQLEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH 2
    化合物114.YaibEGTFTSDK(x18)SIYLEKEAVRLFIEWLIAGGPSSGA-NH 2
    化合物115.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
    化合物116.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC(x18)-NH 2
    化合物117.YaibEGTFTSDK(x20)SIALEEEAVQDFVQWLIAGGPSSGAPPPS-NH 2
    化合物118.YaibEGTFTSDLSC(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
    化合物119.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGK(x20)-NH 2
    化合物120.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSSGA-NH 2
    化合物121.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSS-NH2
    化合物122.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPS-NH 2
    化合物123.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x20)-NH 2
    化合物124.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPS-NH 2
    化合物125.YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSS-NH2
    化合物126.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x18)-NH 2
    化合物127.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物128.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSG-NH 2
    化合物129.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
    化合物130.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAK(x18)-NH 2
    化合物131.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物132.YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSS-NH 2
    化合物133.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPS-NH2
    化合物134.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPC(x18)-NH 2
    化合物135.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物136.YaibEGTFTSDLSIaibLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物137.YaibEGTFTSDLSIALEC(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物138.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAK(x20)-NH 2
    化合物139.YaibEGTFTSDLSIYK(x20)EKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物140.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物141.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPSSG-NH 2
    化合物142.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPK(x18)-NH 2
    化合物143.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
    化合物144.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSS-NH 2
    化合物145.YaibEGTFTSDK(x20)SIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物146.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x20)-NH 2
    化合物147.YaibEGTFTSDC(x18)SIaibLEKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物148.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物149.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
    化合物150.YaibEGTFTSDLSIYK(x18)EKEAVRLFIEWLLAGGPS-NH2
    化合物151.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
    化合物152.YaibEGTFTSDC(x20)SIALEKEAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物153.YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物154.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
    化合物155.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x18)-NH 2
    化合物156.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物157.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x18)-NH 2
    化合物158.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSS-NH2
    化合物159.YaibEGTFTSDLSIAK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物160.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x18)-NH 2
    化合物161.YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGA-NH 2
    化合物162.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGA-NH2
    化合物163.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x20)-NH 2
    化合物164.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物165.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSG-NH 2
    化合物166.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSSGA-NH 2
    化合物167.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSSGA-NH 2
    化合物168.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSS-NH 2
    化合物169.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAPP-NH 2
    化合物170.YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSS-NH 2
    化合物171.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPS-NH 2
    化合物172.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSS-NH2
    化合物173.YaibEGTFTSDLSC(x20)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
    化合物174.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPS-NH2
    化合物175.YaibEGTFTSDLSIALEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物176.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x20)-NH 2
    化合物177.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGA-NH2
    化合物178.YaibEGTFTSDLSIQLEEEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
    化合物179.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
    化合物180.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x18)-NH 2
    化合物181.YaibEGTFTSDLSIaibLEK(x18)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物182.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSS-NH 2
    化合物183.YaibEGTFTSDLSIALEC(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物184.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
    化合物185.YaibEGTFTSDYSIYLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物186.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x18)-NH 2
    化合物187.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物188.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLIAGGPSSGAPPPS-NH 2
    化合物189.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSG-NH 2
    化合物190.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSSGA-NH 2
    化合物191.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
    化合物192.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
    化合物193.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSS-NH 2
    化合物194.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物195.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSS-NH 2
    化合物196.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSSGA-NH 2
    化合物197.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
    化合物198.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAP-NH 2
    化合物199.YaibEGTFTSDLSIALEKEAVK(x20)LFIEWLKAGGPSSGAPPPS-NH 2
    化合物200.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSGAPPPC(x20)-NH 2
    化合物201.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
    化合物202.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSS-NH2
    化合物203.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH 2
    化合物204.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物205.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSS-NH 2
    化合物206.YaibEGTFTSDLSIALEKEAVK(x20)DFVNWLLAGGPSSGAPPPS-NH 2
    化合物207.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x20)-NH 2
    化合物208.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGA-NH 2
    化合物209.YaibEGTFTSDLSIALEKEAVC(x18)LFIEWLIAGGPSSGAPPPS-NH 2
    化合物210.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
    化合物211.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSG-NH 2
    化合物212.YaibEGTFTSDLSIALEKEAVC(x20)LFIEWLIAGGPSSGAPPPS-NH 2
    化合物213.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSS-NH 2
    化合物214.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
    化合物215.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSS-NH 2
    化合物216.YaibEGTFTSDLSIALEKC(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物217.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH 2
    化合物218.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSS-NH 2
    化合物219.YaibEGTFTSDYSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
    化合物220.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLKAGGPS-NH 2
    化合物221.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSSGA-NH 2
    化合物222.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSS-NH 2
    化合物223.YaibEGTFTSDLSIALEKC(x18)AVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物224.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPS-NH 2
    化合物225.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH 2
    化合物226.YaibEGTFTSDLSIaibLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物227.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLLAGGPSSG-NH 2
    化合物228.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSS-NH 2
    化合物229.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSSGA-NH 2
    化合物230.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSS-NH 2
    化合物231.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGA-NH 2
    化合物232.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSS-NH 2
    化合物233.YaibEGTFTSDLSIALEKEAVKEFIAWLK(x20)AGGPSSGAPPPS-NH 2
    化合物234.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPS-NH 2
    化合物235.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSGAPPPS-NH 2
    化合物236.YaibEGTFTSDLSIYLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物237.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
    化合物238.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
    化合物239.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSS-NH 2
    化合物240.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH 2
    化合物241.YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSG-NH 2
    化合物242.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
    化合物243.YaibEGTFTSDLSIQLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
    化合物244.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
    化合物245.YaibEGTFTSDYSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
    化合物246.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPS-NH 2
    化合物247.YaibEGTFTSDLSIALEK(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH 2
    化合物248.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
    化合物249.YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPSSG-NH 2
    化合物250.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
    化合物251.YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPS-NH 2
    化合物252.YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
    化合物253.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
    化合物254.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPPPS-NH 2
    化合物255.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLIAGGPSSGA-NH 2
    化合物256.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSG-NH 2
    化合物257.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLIAGGPSS-NH 2
    化合物258.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
    化合物259.YaibEGTFTSDLSIQLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH 2
    化合物260.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH 2
    化合物261.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLIAGGPS-NH 2
    化合物262.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
    化合物263.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSG-NH 2
    化合物264.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPP-NH 2
    化合物265.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGA-NH 2
    化合物266.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH 2
    化合物267.YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSSGA-NH 2
    化合物268.YaibEGTFTSDLSIQLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
    化合物269.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH 2
    化合物270.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAP-NH 2
    化合物271.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH 2
    化合物272..YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x18)AGGPSS-NH 2
    化合物273.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAK(x20)-NH 2
    化合物274..YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
    化合物275.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGA-NH 2
    化合物276.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH 2
    化合物277.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSS-NH 2
    化合物278.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH2
    化合物279.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPSSG-NH 2
    化合物280.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSGAPPPS-NH 2
    化合物281.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSS-NH 2
    化合物282.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
    化合物283.YaibEGTFTSDLSIaibLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH 2
    化合物284.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
    化合物285.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
    化合物286.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGA-NH 2
    化合物287.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGA-NH 2
    化合物288.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
    化合物289.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x20)-NH 2
    化合物290.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSSGA-NH 2
    化合物291.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSSGA-NH 2
    化合物292.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH 2
    化合物293.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSSGA-NH 2
    化合物294.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSS-NH 2
    化合物295.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSS-NH 2
    化合物296.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
    化合物297.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPP-NH2
    化合物298.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGA-NH 2
    化合物299.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPS-NH 2
    化合物300.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH 2
    化合物301.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH 2
    化合物302.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGA-NH 2
    化合物303.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSSGA-NH 2
    化合物304.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
    化合物305.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH 2
    化合物306.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSG-NH 2
    化合物307.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
    化合物308.YaibEGTFTSDK(x20)SIaibLEKEAVKEFIAWLLAGGPSSGAPPPS-NH 2
    化合物309.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGK(x20)-NH 2
    化合物310.YaibEGTFTSDLSK(x18)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH 2
    化合物311.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
    化合物312.YaibEGTFTSDLSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH 2
    化合物313.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGAPPPS-NH 2
    化合物314.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSGAPPPS-NH 2
    化合物315.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSS-NH 2
    化合物316.YaibEGTFTSDLSIQLEKEAVQDFVNWLIK(x18)GGPSSGAPPPS-NH 2
    化合物317.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSK(x18)-NH 2
    化合物318.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH 2
    化合物319.YaibEGTFTSDLSIQLEEEAVK(x18)EFIAWLLKGG-NH 2
    化合物320.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPK(x18)-NH 2
    化合物321.YaibEGTFTSDLSIQLEKEAVKLFVNWLK(x20)AGGPSSGAPPPS-NH 2
    化合物322.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAP-NH 2
    化合物323.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH 2
    化合物324.YaibEGTFTSDLSIQLEKEAVQDFVNWLK(x18)AGGPSSGAPPPS-NH 2
    化合物325.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSK(x18)-NH 2
    化合物326.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH 2
    化合物327.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGA-NH 2
    化合物328.YaibEGTFTSDK(x18)SIQLEKEAVRLFIEWLLAGGPSS-NH 2
    化合物329.YaibEGTFTSDLSIALEKEAVRLFIEWLK(x18)AGGPSS-NH 2
    化合物330.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH 2
    化合物331.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGA-NH 2
    化合物332.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSS-NH 2
    化合物333.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSS-NH 2
    化合物334.Y(aib)EGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSK(x18)-NH 2
    化合物335.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSS-NH 2
    化合物336.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAP-NH 2
    化合物337.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH 2
    化合物338.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGK(x18)-NH 2
    化合物339.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSS-NH 2
    化合物340.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPSSGA-NH 2
    化合物341.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH 2
    化合物342.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH 2
    化合物343.YaibEGTFTSDLSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH 2
    化合物344.YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLLAGGPSSGA-NH 2
    化合物345.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPS-NH 2
    化合物346.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPP-NH 2
    化合物347.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH 2
    化合物348.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAPPK(x20)-NH 2
    化合物349.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPP-NH 2
    化合物350.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLKAGGPSK(x18)-NH 2
    化合物351.Y(aib)EGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGK(x20)-NH 2
    化合物352.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSS-NH 2
    化合物353.YaibEGTFTSDLSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH 2
    化合物354.YaibEGTFTSDLSSYLEKEAVRLFVQWLKRGGPSSGAPC(x20)-NH 2
    化合物355.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH 2
    化合物356.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLIAGGPSSGAP-NH 2
    化合物357.YaibEGTFTSDLSIYLEEEAAK(x18)EFIAWLLKGGP-NH 2。
  7. 一种药物组合物，其包含前述权利要求任一项的肽化合物或其药学上可接受的盐或溶剂合物，以及药学上可接受的载体或赋形剂。
  8. 前述权利要求1-6任一项的肽化合物或其药学上可接受的盐或溶剂合物或权利要求7所述的药物组合物第一医药用途。
  9. 前述权利要求1-6任一项的肽化合物或其药学上可接受的盐或溶剂合物或权利要求7所述的药物组合物在制备用于治疗或预防下列疾病或状况的药物中的用途：葡萄糖耐量受损(IGT)、高血糖症、1型糖尿病、2型糖尿病、肥胖症、代谢综合征和神经退行性疾病，特别是用于延缓或预防2型糖尿病中的疾病进展，延缓从葡萄糖耐量受损到2型糖尿病的进展；延缓从2型糖尿病到需要胰岛素的糖尿病的进展，治疗代谢综合征，用于调节食欲，诱发饱足感，减少食物摄入，增加能量消耗，治疗肥胖症或预防超重；预防减肥成功后的体重反弹；治疗与超重或肥胖症相关的疾病或状态；治疗贪食症；治疗暴食；治疗血脂异常、动脉粥样硬化、高血压、冠心病、β-阻断剂中毒；非酒精性脂肪性肝病(NAFLD,non-alcoholic fatty liver disease)(可分为单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化)；用于抑制胃肠道的运动；神经退行性疾病如阿兹海默病(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、亨廷顿氏舞蹈病(Huntington's disease)、共济失调(例如脊髓小脑性共济失调)、肯尼迪病(Kennedy disease)、肌强直性营养不良、路易体痴呆症(Lewy body dementia)、多系统萎缩(multi-systemic atrophy)、肌萎缩性脊髓侧索硬化、原发性脊髓侧索硬化、脊髓性肌萎缩、朊病毒相关疾病(例如克雅氏病(Creutzfeldt-Jacob disease))、多发性硬化、毛细血管扩增、贝敦氏症(Batten disease)、皮层基底节变性(corticobasal degeneration)、脊髓亚急性联合变性、脊髓痨、泰-萨二氏病(Tay-Sachs disease)、中毒性脑病、婴儿雷夫叙姆病(infantile Refsum disease)、雷夫叙姆病、神经棘红细胞增多症、尼曼匹克症(Niemann-Pick disease)、莱姆病(Lyme disease)、马查多·约瑟夫病(Machado-Joseph disease)、桑德霍夫病(Sandhoff disease)、雪-杜二氏综合征(Shy-Drager syndrome)、刺猬摇摆综合征(wobbly hedgehog syndrome)、原发病(proteopathy)、脑β-淀 粉样脑血管病、青光眼中的视网膜神经节细胞变性、核蛋白病(synucleinopathies)、滔蛋白病(tauopathies)、额颞叶变性(FTLD)、痴呆症、Cadasil综合征、具有淀粉样变性的遗传性脑溢血、亚历山大病(Alexander disease)、seipinopathies、家族性淀粉样变性神经病变、老年系统性淀粉样变性(senile systemic amyloidosis)、serpinopathies、AL(轻链)淀粉样变性(原发性全身淀粉样变性)、AH(重链)淀粉样变性、AA(继发性)淀粉样变性、主动脉内淀粉样变性(aortic medial amyloidosis)、ApoAI淀粉样变性、ApoAII淀粉样变性、ApoAIV淀粉样变性、芬兰型家族性淀粉样变性(FAF)、溶菌酶淀粉样变性、纤维蛋白原淀粉样变性、透析淀粉样变性、包涵体肌炎/肌病、白内障、具有视紫红质突变的视网膜色素变性、甲状腺髓样癌、心脏心房淀粉样变性、垂体催乳素瘤、遗传性网格状角膜营养不良(Hereditary lattice corneal dystrophy)、皮肤性苔藓状淀粉样变性、马洛里小体(Mallory bodies)、角膜乳铁蛋白淀粉样变性、肺泡蛋白沉着症(pulmonary alveolar proteinosis)、牙原性(Pindborg)肿瘤淀粉体、囊性纤维化病、镰状细胞疾病或危重病性肌病(CIM)、骨骼相关的病症。
  10. 根据权利要求9的用途，其中所述用途是制备用于减肥的药物。
  11. 前述权利要求1-6任一项的肽化合物或其药学上可接受的盐或溶剂合物或权利要求7所述的药物组合物在制备用于降低血脂的药物中的用途，优选降低选自下列的血脂成分：胆固醇、甘油三酯、游离脂肪酸、低密度脂蛋白胆固醇。
  12. 前述权利要求1-6任一项的肽化合物或其药学上可接受的盐或溶剂合物或权利要求7所述的药物组合物在制备用于降血糖或治疗糖尿病的药物中的用途。
  13. 权利要求1-6任一项的肽化合物的制备方法，其中所述制备方法是通过化学合成的方法。
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