Human amylin analogue as well as derivative and application thereof

Abstract

The invention relates to a polypeptide analogue or a derivative thereof as well as a preparation method and application thereof, in particular to an agonistic polypeptide analogue of an insulin amyloid polypeptide receptor or a derivative thereof. The polypeptide analogue or the derivative thereof provided by the invention has good agonism on an insulin amyloid polypeptide receptor, has the characteristics of good stability, high activity and the like, and can be used for treating and preventing diseases related to the insulin amyloid polypeptide receptor, such as abnormal weight, especially obesity and overweight.

Description

Human amylin analogs, derivatives and uses thereof Technical Field

[0001] The present application relates to the field of biomedicine or biopharmaceutical technology, and more specifically to human amylin analogs and derivatives and their use in treating and / or preventing diseases related to amylin or metabolism. Background Art

[0002] Amylin, also known as islet amyloid polypeptide (IAPP), is a member of the calcitonin gene-related peptide (CGRP) family. It exerts its physiological functions by activating corresponding receptors and has many functions such as regulating blood sugar, controlling food intake, and regulating metabolism. However, amylin is easily fibrotic and forms amyloid deposits under neutral or alkaline conditions. At the same time, amylin has a short retention time in the blood, with a half-life of only about 13 minutes, which limits its use in the treatment of diseases. Therefore, the development of amylin analogs with better stability, longer half-life, and more obvious therapeutic effects is of great significance for the treatment of metabolic diseases such as diabetes and obesity.

[0003] Pramlintide (also known as Symlin) is an amylin analog. By replacing amino acid residues 25, 28, and 29 with Pro, its stability in solution is improved. It is currently approved for the treatment of diabetes. However, pramlintide has a half-life of only approximately 48 minutes, requiring frequent injections to maintain efficacy. It easily aggregates and precipitates at neutral pH, limiting its combined use with other therapeutic drugs. WO2012162542A1 discloses a derivative of an amylin polypeptide analog that is substituted with lysine and linked to polyethylene glycol to extend the duration of action of amylin or its analog in the body. However, the PEGylated derivative has a significantly reduced affinity for the amylin receptor. Li-Mei Yan et al. (Proc Natl Acad Sci, 2006, 103(7):2046-2051) disclosed an amylin derivative, IAPP-GI, which improves its solubility by methylating 24-Gly and 26-Ile, but its activity is reduced compared to the wild-type. Cagrilintide is a long-acting amylin derivative developed by Novo Nordisk and is currently in Phase II clinical trials.

[0004] Although the amylin analogs / derivatives in the prior art have been improved in terms of solubility, stability, half-life, activity, etc. compared with amylin, there are still technical problems such as insufficient in vivo efficacy and insufficient drug stability. Therefore, further improvement of amylin derivatives is still needed.

[0005] Summary of the Invention

[0006] The present application provides a new amylin analog, and derivatives of the analog, a preparation method, a pharmaceutical composition and a product comprising the polypeptide or its derivatives, and their use in preventing and / or treating diseases.

[0007] In one aspect, the present application provides a novel amylin analog or a pharmaceutically acceptable salt thereof, the analog comprising X1CNTA TCATQ RLAX 14 F LX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 T NVGSX 35 TX 37 The amino acid sequence of [Formula (I)] comprises one or more amino acid mutations at positions 1, 14, 17, 19, 20, 21, 22, 23, 24, 25, 28, 29, 35, and 37, wherein X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R, or deleted, and X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 19 Select from S or K, X 20 Selected from S or K, X 21 Select from N or K, X 22 Select from N or K, X 23 Selected from F, L or K, X 24 Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 35 Selected from N or G, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp.

[0008] In some preferred embodiments, the amylin analog comprises X1CNTA TCATQ RLAX 14 FLX 17 HSS NNX 23 X 24 X25 ILX 28 X 29 T NVGSN TX 37 The amino acid sequence represented by [Formula (II)] comprises one or more amino acid mutations at positions 1, 14, 17, 23, 24, 25, 28, 29, and 37,

[0009] Preferably, X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deletion, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp;

[0010] Preferably, X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp;

[0011] Preferably, X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deletion, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29Selected from S or P, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp;

[0012] Preferably, X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp;

[0013] Preferably, X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deletion, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 is P or trans-Hyp;

[0014] Preferably, X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 is P or trans-Hyp;

[0015] Particularly preferably, X1 is selected from K or R, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Selected from G, R or K, X 25 Selected from A or P, X28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, P or trans-Hyp;

[0016] More preferably, X1 is K, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Selected from G, R or K, X 25 Selected from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, P or trans-Hyp;

[0017] More preferably, X1 is R, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Selected from G, R or K, X 25 Selected from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, P or trans-Hyp;

[0018] More preferably, X1 is selected from K or R, X 14 It's D, X 17 It's R, X 23 It's L, X 25 It's P, X 24 Selected from G, R or K, X 28 It's P, X 29 It's P, X 37 is P or trans-Hyp;

[0019] More preferably, X1 is K, X 14 It's D, X 17 It's R, X 23 It's L, X 24 Select from G or K, X 25 It's P, X 28 It's P, X 29 It's P, X 37 is P or trans-Hyp;

[0020] Most preferably, X1 is K, X 14 It's D, X 17 It's R, X 23 It's L, X 24 It's K, X 25 It's P, X 28It's P, X 29 It's P, X 37 It is P or trans-Hyp.

[0021] In one aspect, the present application provides a novel amylin analog derivative or a pharmaceutically acceptable salt thereof, wherein the amylin analog derivative has one or more amino acid modifications and comprises the polypeptide sequence of the amylin analog described above.

[0022] In some embodiments, the polypeptide analogs or derivatives described herein comprise the amino acid sequences of SEQ ID NOs. 2-104 in Table 1.

[0023] Table 1

[0024] In some embodiments, the derivative sequence of the polypeptide analog described in the present application includes 1-10 amino acid modifications compared to the wild-type polypeptide sequence, preferably, includes 1-8 amino acid modifications, further preferably, includes 1-4 amino acid modifications, more preferably, includes 2 amino acid modifications, and most preferably, includes 1 amino acid modification.

[0025] In some embodiments, the amino acid modification of the derivative sequence of the polypeptide analogue compared to the wild-type polypeptide sequence is a natural amino acid or a non-natural amino acid, including but not limited to the introduction of a functional group that can be used for coupling on the side chain of glutamic acid, aspartic acid, lysine, glutamine or asparagine. Preferably, the amino acid modification is on the side chain of lysine. Preferably, the lysine is located in the first position of the polypeptide derivative, and the modified side chain is selected from the Alpha-amino or Epsilon-amino side chain of lysine, preferably the Epsilon amino side chain.

[0026] In some embodiments, the coupled functional group includes an extension portion and a linker connecting the extension portion and the modified amino acid, wherein the linker can be composed of one or more linkers, and the connection order of the linkers is arbitrary. As long as the connection between the extension portion and the modified amino acid can be achieved, it should be understood as a form within the scope of this application.

[0027] In a preferred embodiment, the single linker can be the following structure:

[0028]

[0029]

[0030] Wherein, m is 0, 1, 2 or 3; n is 1, 2 or 3; s is any integer from 0 to 6; and p is any integer from 1 to 8.

[0031] Preferably, the linker is:

[0032] Wherein m is 1 or 2; n is 1 or 2; and p is any integer from 1 to 5.

[0033] More preferably, the linker is:

[0034] Where p is any integer from 1 to 5.

[0035] Preferably, p is 1 and the linker is γGlu.

[0036] In a preferred embodiment, the extension is:

[0037] Where x is any integer from 4 to 38;

[0038] Preferably, the extension portion is Where x is any integer from 4 to 38.

[0039] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0040] Wherein, X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37is selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp; the linker is:

[0041] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0042] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0043] wherein X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deleted, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Select from S or P, X 37 is selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp; the linker is:

[0044] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0045] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0046] Wherein, X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 is selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp; particularly preferably, X1 is selected from K or R, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Select from G or K, X 25 Selected from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y or trans-Hyp; the linker is:

[0047] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0048] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0049] Among them, X1 is K, X 14 Select from N or D, X 17 Selected from V or R, X23 Select from F or L, X 24 Select from G or K, X 25 Selected from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y or trans-Hyp; the linker is:

[0050] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0051] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0052] Among them, X1 is R, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Select from G or K, X 25 Selected from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y or trans-Hyp; the linker is:

[0053] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0054] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0055] Wherein, X1 is selected from K or R, X 14 It's D, X 17 It's R, X 23 It's L, X 25 It's P, X 24 Select from G or K, X 28 It's P, X 29 It's P, X 37 is trans-Hyp; the linker is:

[0056] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0057] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0058] Among them, X1 is K, X 14 It's D, X 17 It's R, X 23 It's L, X 24 Select from G or K, X 25 It's P, X 28 It's P, X 29 It's P, X 37 is trans-Hyp; the linker is:

[0059] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0060] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0061] Among them, X1 is K, X 14 It's D, X 17 It's R, X 23 It's L, X 24 It's K, X 25 It's P, X 28 It's P, X 29 It's P, X 37 is trans-Hyp; the linker is:

[0062] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0063] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0064] X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deleted, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24Selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 is P or trans-Hyp; the linker is:

[0065] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0066] Preferably, the amino acid sequence of the polypeptide analog comprises the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I),

[0067] X1 is selected from K or R, X 14 Selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 23 Selected from F, L or K, X 24 Selected from G, R or K, X 25 Select A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 is P or trans-Hyp; the linker is:

[0068] wherein m is 1 or 2; n is 1 or 2; p is any integer from 1 to 5; the extended portion is Where x is any integer from 4 to 38.

[0069] In some embodiments, the polypeptide analog derivatives of the present application are selected from the following compounds shown in Table 2, wherein PD065 is a Cagrilintide molecule.

[0070] Table 2.

[0071] Compounds PD001-PD198 represent polypeptide derivatives obtained by modifying an amino acid sequence with a fatty acid-containing side chain, i.e., a functional group that can be used for coupling is introduced into the amino acid side chain for amino acid modification in this application, such as the derivatives obtained by modifying the corresponding polypeptide sequence with the corresponding fatty acid-containing side chain in Table 2. For example, PD001 represents a derivative obtained by modifying the amino acid K at position 21 of the sequence RCNTATCATQRLAEFLRHSSKNLGPILPPTNVGSNTP-NH2 with a functional group that can be used for coupling, i.e., a side chain (2*AEEA+γGlu+C20diacid). Typically, the C16-C22 fatty diacid moiety is located outside the fatty acid-containing side chain used for modification relative to the amino acid sequence, at the distal end where the side chain is connected to the amino acid sequence.

[0072] In some embodiments, the derivatives of the polypeptide analogs of the present application are preferably selected from the following derivatives:

[0073] PD069, PD070, PD071, PD072, PD140, PD158, PD160, PD161, PD144, PD145, PD146, PD147, PD187.

[0074] In some embodiments, the derivative of the polypeptide analog of the present application is compound PD069, and the structure of PD069 is shown below:

[0075] In some embodiments, the derivative of the polypeptide analog of the present application is compound PD070, and the structure of PD070 is shown below:

[0076] In some embodiments, the derivative of the polypeptide analog of the present application is compound PD071, and the structure of PD071 is shown below:

[0077] In some embodiments, the derivative of the polypeptide analog of the present application is compound PD072, and the structure of PD072 is shown below:

[0078] One aspect of the present application also relates to a method for preparing the novel amylin analog or its derivative.

[0079] In some embodiments, the preparation of the new amylin analogs or derivatives thereof can be prepared by conventional methods known to those skilled in the art. Generally, polypeptide molecules can be prepared by chemical synthesis methods or biological fermentation methods, or a combination of the two. For example, during the polypeptide synthesis process, the polypeptide gene sequence can be synthesized, and the corresponding polypeptide gene with a tag is inserted into the plasmid by conventional genetic engineering methods to construct an expression plasmid, and the expression plasmid is transferred into competent cells to construct expression cells. After screening, the expression cells containing the target polypeptide gene are fermented under suitable culture conditions, the fermentation products are collected and the target polypeptide is finally obtained by purification methods. Furthermore, the amino acid side chains of the target polypeptide can be modified by chemical modification methods, and purified to obtain derivatives of the polypeptide analogs.

[0080] In one aspect, the present application also relates to a drug or pharmaceutical composition comprising the above-mentioned amylin analog or derivative thereof and a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the pharmaceutical compositions described herein further include one or more oral delivery agents, preferably N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC) salts, more preferably PNAC, i.e., potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. The NAC salt or PNAC salt of the oral delivery agent described herein should be understood to be any crystalline form that can meet the oral delivery requirements of the composition of this application, such as those described in CN112661663B.

[0082] The structure of the PNAC salt is shown in formula (II):

[0083] The structure of the NAC salt is shown in formula (I):

[0084] In some embodiments, the pharmaceutical composition described herein further includes one or more other pharmacologically active substances.

[0085] In some embodiments, the composition described herein further comprises a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient includes, but is not limited to, one or more of the following: a pharmaceutically acceptable carrier, a stabilizer, a dispersant, a solubilizer, a plasticizer, etc. Generally, these substances are non-toxic, inert, and pharmaceutically acceptable inactive substances.

[0086] In one aspect, the present application provides use of the above-mentioned amylin analogs or derivatives thereof, and pharmaceutical compositions of the present application in the preparation of medicaments for preventing and / or treating diseases. Preferably, the use includes use in the preparation of medicaments for preventing and / or treating amylin receptor-related diseases. Further preferably, the use includes use in the preparation of medicaments for preventing and / or treating fat metabolism disorders, blood sugar metabolism disorders, cardiovascular diseases, brain system diseases, mental system diseases or nervous system diseases, including but not limited to abnormal weight, hyperlipidemia, hypertension, arteriosclerosis, fatty liver, dyslipidemia, cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia and gastrointestinal ulcers, hyperglycemia, diabetes, impaired glucose tolerance, syndrome X, cognitive impairment, and stroke. Preferably, the disease is abnormal weight or blood sugar metabolism disorders. Further preferably, the disease is abnormal weight, including but not limited to obesity or overweight.

[0087] In one aspect, the present application provides a method for preventing and / or treating a disease, comprising administering the amylin analog or derivative thereof, the drug or pharmaceutical composition described herein to a subject in need thereof, wherein the disease is an amylin receptor-related disease, preferably, dyslipidemia, dysglycemic metabolism, cardiovascular disease, brain system disease, mental system disease or nervous system disease, including but not limited to abnormal weight, hyperlipidemia, hypertension, arteriosclerosis, fatty liver, dyslipidemia, cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia and gastrointestinal ulcer, hyperglycemia, diabetes, impaired glucose tolerance, syndrome X, cognitive impairment, and stroke. Further preferably, the disease is abnormal weight or dysglycemic metabolism, and more preferably, the disease is abnormal weight, including but not limited to obesity or overweight.

[0088] The amylin analogs or derivatives thereof, drugs or pharmaceutical compositions described herein may also be administered in combination with one or more other pharmacologically active substances, including but not limited to weight regulators, anti-obesity agents, lipid metabolism regulators, blood sugar regulators, hypertension therapeutic agents, cardiovascular regulators, brain system diseases, mental system diseases or nervous system regulators. Preferably, the pharmacologically active substances are selected from: GLP-1 receptor agonists (including but not limited to GLP-1, GLP-1 analogs, GLP-1 derivatives), GIP receptor agonists (including but not limited to GIP, GIP analogs, GIP derivatives), insulin receptor agonists (including but not limited to insulin, insulin analogs, insulin derivatives).

[0089] Effects of the Invention

[0090] The polypeptide analogs or derivatives provided in this application have good agonism to the insulin amyloid polypeptide receptor, and are characterized by good stability and high activity, and can be used to treat and prevent diseases related to the insulin amyloid polypeptide receptor, such as abnormal body weight, especially obesity and overweight. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] The accompanying drawings are provided to facilitate a better understanding of the present application and are not intended to limit the present application.

[0092] FIG1 shows the stability test results of compounds PD065, PD069, PD070, PD071, and PD072 at 40 degrees Celsius on day 0, day 7, and day 15, respectively.

[0093] FIG2A shows the temporal trend of the weight loss effects of different derivatives in SD rats.

[0094] FIG2B shows the temporal trends of the effects of different derivatives on food intake in SD rats.

[0095] FIG2C shows the body weight change rate of SD rats in group A treated with different derivatives at 48 hours.

[0096] FIG2D shows the body weight change rate of SD rats in group B treated with different derivatives at 48 hours.

[0097] FIG3A shows the temporal trend of the weight loss effects of compounds PD065 and PD069 at different concentrations in SD rats.

[0098] FIG3B shows the temporal trend of the weight loss effects of compounds PD065 and PD070 at different concentrations in SD rats.

[0099] FIG3C shows the temporal trend of the weight loss effects of compounds PD065 and PD071 at different concentrations in SD rats.

[0100] FIG3D shows the temporal trend of the weight loss effects of compounds PD065 and PD072 at different concentrations in SD rats.

[0101] FIG4A shows the temporal trend of the effects of compounds PD065 and PD071 at different concentrations on food intake in SD rats.

[0102] FIG4B shows the temporal trend of the effects of each derivative treatment group at different concentrations on the food intake of SD rats.

[0103] FIG5A shows the temporal trend of the weight loss effects of compounds PD065 and PD187 in SD rats.

[0104] FIG5B shows the temporal trend of the weight loss effects of the corresponding compounds in SD rats.

[0105] FIG5C shows the temporal trends of the effects of the corresponding compounds on food intake in SD rats.

[0106] FIG6 shows the pharmacokinetics of each polypeptide after oral administration of oral delivery compositions containing different polypeptide derivatives in beagle dogs. DETAILED DESCRIPTION

[0107] The following description of exemplary embodiments of the present application includes various details of the embodiments of the present application to facilitate understanding, and should be considered as merely exemplary. Therefore, those skilled in the art will recognize that various changes and modifications may be made to the embodiments described herein without departing from the scope and spirit of the present application. Similarly, for the sake of clarity and conciseness, descriptions of well-known functions and structures are omitted in the following description.

[0108] abbreviation

[0109] The corresponding names or structural forms of some abbreviations used in the examples of this application are shown in Table 3 below:

[0110] Table 3.

[0111] AA: Amino Acid; Boc: t-Butyloxy carbonyl; DCM: dichloromethane; DMF: N,N-Dimethyl formamide; DIEA: N,N-Diisopropylethylamine; EDT: 1,2-Ethanedithiol; Fmoc: 9-fluorenylmethyloxycarbonyl; OtBu: tert-butyl ester; Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl chloride; Pip: Piperidine; TBTU: O-(Benzotriazol-l-yl)-N,N,N,N,-tetramethyluronium Tetrafluoroborate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate; tBu: tertiary butyl; TFA: Trifluoroacetic acid; TIS: Triisopropylsilane; Trt: Triphenylmethyl.

[0112] definition

[0113] "Amylin" or "Amylin polypeptide" or "amylin" or "amylin polypeptide" as used herein refers to a variant / analog, fragment or fusion protein having the sequence of Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr or the above sequence that substantially retains the amylin receptor agonist effect.

[0114] The "analog" mentioned herein refers to a compound in which at least one amino acid residue of a specific polypeptide molecule has been replaced by another amino acid residue, and / or at least one amino acid residue has been deleted, and / or at least one amino acid residue has been added to the N-terminus or C-terminus, and / or at least one amino acid residue has been inserted between any two amino acids.

[0115] Unless the context clearly indicates otherwise, the names of specific polypeptides, such as "Amylin", and the terms "polypeptide", "analog", and "variant" are interchangeable in this application.

[0116] As used herein, "derivatives" refer to products obtained by modifying functional groups (e.g., amino acid residues) of biomacromolecules (e.g., polypeptides and proteins) with certain compounds or molecules. Such modifications include, but are not limited to, acylation, amidation, esterification, and thioesterification.

[0117] The pharmaceutical composition according to the present application can be administered by any suitable route, for example, orally, nasally, intradermally, subcutaneously, intramuscularly or intravenously.

[0118] The "fat metabolism disorder" related diseases described in this application are a general term for related diseases caused by fat metabolism disorders. Common ones include abnormal weight, such as obesity, and also include: hyperlipidemia, hypertension, atherosclerosis, fatty liver, cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, indigestion and gastrointestinal ulcers, etc.

[0119] As used herein, "abnormal weight" refers to a subject's weight assessment indicator being outside the normal average range for their population, using the same assessment system. In certain embodiments, the abnormal weight refers to obesity. In certain embodiments, "weight loss" refers to being overweight or reducing obesity.

[0120] Example

[0121] The present application can be better understood with reference to the following examples. However, it should be understood that the following examples are for illustrative purposes only and should not be construed as limiting the scope of protection of the present application in any way. Unless otherwise specified, the methods listed in the experimental manuals such as the "Molecular Cloning Experiment Guide" and the "Cell Experiment Guide" familiar to those skilled in the art and the CFDA's experimental guidelines can be implemented. Among them, the reagents and raw materials used are all commercially available and can be purchased through public channels.

[0122] Example 1 Preparation of Amylin Derivatives

[0123] Solid-phase organic synthesis, Fmoc-protected amino acid strategy, and SPPS solid-phase synthesis technology are used to complete peptide synthesis, cleavage, oxidation, and purification to obtain the target product.

[0124] Taking compound PD065 (Cagrilintide) as an example, its structural formula is as follows:

[0125] The synthesis process is as follows:

[0126] Solid phase synthesis: using Fmoc-Linker MBHA Resin S = 0.32 mmol / g, adopting Fmoc / tBu process, according to the above sequence, amino acids were condensed and linked in sequence from C-terminus to N-terminus (from right to left) using the method in Table 4.

[0127] Table 4. Synthesis procedures list

[0128] The amino acid coupling sequence is shown below:

[0129] A-01Fmoc-Pro-OH, A-02Fmoc-Thr(tBu)-OH, A-03Fmoc-Asn(Trt)-OH, A-04Fmoc-Ser(tBu)-OH, A-05Fmoc-Gly-OH, A -06Fmoc-Val-OH, A-07Fmoc-Asn(Trt)-OH, A-08Fmoc-Thr(tBu)-OH, A-09Fmoc-Pro-OH, A-10Fmoc-Pro-OH, A-11Fmo c-Leu-OH, A-12Fmoc-Ile-OH, A-13Fmoc-Pro-OH, A-14Fmoc-Gly-OH, A-15Fmoc-Phe-OH, A-16Fmoc-Asn(Trt)-OH, A- 17Fmoc-Asn(Trt)-OH, A-18Fmoc-Ser(tBu)-OH, A-19Fmoc-Ser(tBu)-OH, A-20Fmoc-His(Trt)-OH, A-21Fmoc-Arg(Pb f)-OH, A-22Fmoc-Leu-OH, A-23Fmoc-Phe-OH, A-24Fmoc-Glu(OtBu)-OH, A-25Fmoc-Ala-OH, A-26Fmoc-Leu-OH, A-27 Fmoc-Arg(Pbf)-OH, A-28Fmoc-Gln(Trt)-OH, A-29Fmoc-Thr(tBu)-OH, A-30Fmoc-Ala-OH, A-31Fmoc-Cys(Trt)-OH, A-32Fmoc-Thr(tBu)-OH, A-33Fmoc-Ala-OH, A-34Fmoc-Thr(tBu)-OH, A-35Fmoc-Asn(Trt)-OH, A-36Fmoc-Cys(Trt)-OH, A-37Fmoc-Lys(Boc)-OH, A-38Fmoc-Glu-otbu, A-39C20diacid; finally, the polypeptide derivative resin is formed, and the polypeptide derivative resin (peptide resin) is washed, transferred out, and dried to constant weight for cleavage.

[0130] Peptide resin cleavage:

[0131] Preparation of cleavage reagent: Calculate the amount of cleavage reagent based on a volume ratio of 1g peptide resin to 10ml ± 2ml: TFA:H2O:EDT:TIS = 95:1:2:2. Add the required cleavage reagents, H2O, TFA, EDT, and TIS, to the cleavage reaction flask in sequence, maintaining the temperature between 0 and 10°C. Stir the cleavage reagents to the peptide resin, and after the system temperature stabilizes, continue stirring at 25-30°C for 2.5 hours. Filter the cleavage reagent and precipitate it with 5 volumes of glacial ether. Filter the precipitate and wash it three times with 3 volumes of glacial ether. Dry under reduced pressure at room temperature to obtain a crude solid.

[0132] Peptide oxidation: Grind the crude product into powder, prepare purified water, slowly add the ground crude product while stirring, and at the same time dropwise add acetonitrile aqueous solution. After the crude product is added and completely dissolved, add iodine methanol solution and stir for half an hour.

[0133] Purification and Lyophilization: The oxidized liquid is filtered through a 0.45 μm microporous membrane. The crude product is purified using a C-18 preparative column using an appropriate gradient at room temperature. The target product is collected, analyzed, tested, and classified. Purity is required to be ≥90%. Unqualified target products are collected and further purified using an appropriate gradient. The qualified liquid peak is collected. The qualified liquid sample is then freeze-dried under reduced pressure to obtain a powdered, purified polypeptide lyophilized powder.

[0134] The compounds described in Table 2 were prepared using methods and steps similar to those of the compound PD065 (Cagrilintide).

[0135] Example 2 In vitro efficacy test of amylin derivatives

[0136] The purpose of this study was to test the activity or potency of amylin derivatives at the human amylin receptor in vitro using a luciferase assay.

[0137] 2.1 Construction of the Amylin Receptor / CRE-luc Cell Line

[0138] Using standard methods, CHO-K1 / Ga15 / AMY3 cells (calcitonin receptor and receptor-activating modified peptide RAMP have been constructed and purchased from GenScript) were transfected with a plasmid containing multiple copies of a cAMP response element (CRE)-driven luciferase expression cassette and cultured in F12 medium containing Zeocin 200 ug / mL, puromycin (2 ug / mL), hygromycin (100 ug / mL) and G418 (400 ug / mL) to obtain a stably transfected amylin receptor / CRE-luc cell line.

[0139] 2.2 Amylin-luciferase assay

[0140] 50 μL of growth medium (F12 medium containing 10% FBS) was added to each well of a white 96-well plate, and stably transfected amylin / CRE-luc CHO cells were seeded into the white 96-well culture plate at a density of approximately 20,000 cells / well for activity assay.

[0141] The lyophilized powder obtained in Example 1 was dissolved in 20 mM phosphate buffer at pH 7.0 and diluted with F12 medium containing 10% FBS to obtain an initial concentration of 100 nM of the derivative sample. The derivative sample was then graded diluted with F12 medium containing 10% FBS to obtain a concentration ranging from 100 nM to 100 nM. -5 Seven sample concentrations, each with a 10-fold difference in nM concentration, were added to each well. 50 μL of the sample assay solution of the corresponding concentration was added and incubated at 37°C and 5% CO₂ for 24 hours. Luciferase (100 μL) was then added to each well and incubated for 3 minutes. Luminescence was measured using SoftMax Pro 7.0.3 GxP software on a SpectraMax L (Molecular Devices). A standard curve was plotted based on the fluorescence values, and the EC₅₀ was calculated. The results are shown in Table 5.

[0142] Table 5.

[0143] The results in Table 5 show that the polypeptide derivatives of the present application have good activity against human amylin receptor.

[0144] Example 3 Freeze-thaw stability of derivatives

[0145] The lyophilized powder of the peptide analog derivative prepared in Example 1 was prepared by mixing the buffer solution at a mass-to-volume ratio of 0.2 mg / ml. The peptide was dissolved in 20 mM phosphate buffer (PB) (pH 7.0). The sample was stored at -20°C overnight and then removed and allowed to thaw at room temperature. During the experiment, changes in the peptide properties after dissolution and after freezing and thawing were observed and recorded. The peptide concentration before and after freeze-thaw was determined using the following liquid chromatography method:

[0146] Materials and equipment: High-performance liquid chromatography (Agilent 1200), ultrapure water (18.2 MΩ homemade ultrapure water), acetonitrile (HPLC grade), trifluoroacetic acid (HPLC grade); reversed-phase chromatography column: Sepax Bio-C4 4.6*100 mm 5 μm

[0147] Sample Preparation: Weigh a certain amount of peptide and dissolve it in 20mM PB, pH 7.4 buffer. If the solubility is poor, add a small amount of 0.1M NaOH to adjust the pH to 8.0 to completely dissolve it. Control the concentration between 0.5-2mg / ml. Take the sample to be tested and centrifuge it at 10,000 rpm, 4°C, for 3 minutes. Transfer the supernatant to a liquid phase injection vial.

[0148] Chromatographic conditions: Flow rate: 1.0 ml / min; Autosampler temperature: 15°C; Column temperature: 15°C; Detection wavelength: 280 nm; Mobile phase A: 100% H2O + 0.05% TFA; Mobile phase B: 100% ACN. Elution gradient is shown in the table below:

[0149] Table 6 Liquid chromatography elution gradient list

[0150] The freeze-thaw yield was calculated using the following formula: freeze-thaw yield = polypeptide concentration after freeze-thaw / polypeptide concentration before freeze-thaw.

[0151] Table 7

[0152] As shown in Table 7, most of the polypeptide derivatives of the present application have good freeze-thaw stability and yield.

[0153] Example 4: Stability study of derivatives at 40°C

[0154] Compounds PD065, PD069, PD070, PD071, and PD072 were mixed at 1.34 mg / ml with sodium dihydrogen phosphate (1.42 mg / ml) and dissolved in ultrapure water. The pH was adjusted to approximately 7.4 using hydrochloric acid / sodium hydroxide. The solution was then filtered through a 0.22 μm sterile filter in a clean bench and transferred into sterilized vials. The vials were capped and placed in a 40°C stability test chamber.

[0155] Before testing, the sample was centrifuged at 10,000 rpm, 4°C, for 3 min, and the supernatant was transferred to a liquid phase injection bottle. The liquid phase method in Example 3 was used for testing. The results are shown in Table 8 and Figure 1

[0156] Table 8

[0157] As shown in the results of Table 8, compared with the thermal stability change of PD065, the thermal stability of the polypeptide derivatives of the present application is basically equivalent to it, and surprisingly, the compound PD070 shows an extremely low percentage decrease in protein concentration.

[0158] Example 5 Study on the Weight Loss Efficacy of Derivatives

[0159] Sprague Dawley (SD) rats weighing 200-250 g were selected for this experimental study. Prior to the start of the experiment, the rats were allowed to acclimate to the experimental environment for at least 10-14 days. During this period, the rats were housed for two weeks on arrival under a reversed light / dark cycle (meaning the lights were off during the day and on at night) and housed individually for the first week of arrival to ensure data accuracy and high test sensitivity. The rats had free access to food and water throughout the acclimatization and experimental periods. The derivative test was divided into experimental groups A: A1, A2, A3, A4, A5, A6, and Group B: B1, B2, B3, B4, B5. Each derivative test group consisted of 5-8 rats, and each group of rats was subcutaneously administered a 30 nmol / kg dose of the derivative or vehicle. The dosing time for each group was recorded. After dosing, the rats were returned to their home cages, where they had access to food and water. Food consumption and rat weight changes were recorded every 24 hours using online or manual recording.

[0160] The changes in body weight and food intake of SD mice in each group are shown in Figures 2A-2D and Tables 9-10.

[0161] Table 9

[0162] Table 10

[0163] The experimental results show that compared with the weight loss effect of PD065, the polypeptide derivatives of the present application show higher weight loss ability, even reaching more than twice the effect of PD065.

[0164] Example 6 Study on the effect of dosage of derivatives on weight loss

[0165] SD rats obtained using the same method as in Example 5 were used in this experimental study. The derivative test was divided into experimental groups C: C1-C13, and D: D1-D7, with 5-8 rats in each derivative test group. The rats in each group were subcutaneously administered with a dose of 10 nmol / kg, 20 nmol / kg, or 30 nmol / kg of the derivative or the vehicle, as described in Tables 11 and 12. The dosing time for each group was recorded. After dosing, the rats were returned to their home cages, where they had access to food and water. Food consumption and rat body weight changes were recorded every 24 hours by online recording or manual recording.

[0166] The changes in body weight and cumulative food intake of SD mice in each group are shown in Figures 3A-3D, 4A-4B and Tables 11 and 12.

[0167] Table 11

[0168] Table 12

[0169] Judging from the experimental results, the polypeptide derivative molecule of the present application has a better weight loss effect than PD065 (Cagrilintide) under the same conditions.

[0170] Example 7. Study of derivative fatty acid side chains

[0171] SD mice obtained using the same method as in Example 5 were used for this experimental study. The derivative test was divided into experimental group E: the weight loss effect of test compounds PD065 and PD187, and experimental group F, test compounds PD065, PD071, PD140, PD144, PD145, PD146 and PD147, with 5-8 rats in each derivative test group, and each group of rats was subcutaneously administered a 30nmol / kg dose of the derivative or solvent. The administration time of each group was recorded. After administration, the rats were returned to their home cages, and then food and water that they could obtain were placed in them. Food consumption and rat weight changes were recorded every 24 hours by online recording or manual recording. The results of experimental group E are shown in Figure 5A, and the results of experimental group F are shown in Figures 5B and 5C.

[0172] Animal experiment results showed that when the N-terminus was R (PD140), the activity was better than that of PD065.

[0173] To further evaluate the effect of fatty acid side chains on peptide activity, PD071 (SEQ ID NO. 3) was used as the peptide backbone. The results showed that when different fatty acid linkers were used, such as 2AEEA+C20 diacid (PD187), αAsp+C20 diacid (PD144), βAsp+C20 diacid (PD145), Trx+C20 diacid (PD146), and Inp+C20 diacid (PD147), their activities were all better than PD065.

[0174] Example 8: Preparation of Fatty Acid Side Chain-Containing Polypeptide Derivative Tablets

[0175] The polypeptide derivatives containing fatty acid side chains are prepared into oral tablets, which contain the same amount of oral delivery agent PNAC. The preparation method of PNAC is as follows:

[0176] N-[8-(2-Hydroxybenzoyl)amino]octanoic acid (NAC) was prepared according to the method described in Example 1 of International Patent Application WO2008 / 028859. Isopropyl alcohol (22070.0 ml, 4.0 vol) was added to a 50 L reactor. Stirring was initiated, and NAC (5518 g, 1.0 eq) was added. The system was heated to 50°C, and a 50% potassium hydroxide solution (1304.0 g, 1.0 eq) was added dropwise. The solution became a clear, transparent yellow solution, which was then maintained at 50°C for 1 h. The reaction solution was concentrated in batches at 40°C to yield a light orange-yellow crude product.

[0177] The crude product was slurried in isopropanol (19310.0 ml, 3.5 vol) for 1 hour. The mixture was filtered, and the filter cake was rinsed with isopropanol (2760.0 ml, 0.5 vol). The filter cake was transferred to a vacuum drying oven, dried at 60°C under nitrogen pressure for 16 hours, and then transferred to a vacuum drying oven at 100°C for 24 hours. After drying, 4.52 kg of the product (72.8% yield) was obtained as an off-white powdery solid, namely PNAC.

[0178] The contents of the main components in the fatty acid side chain-containing polypeptide derivative tablets are shown in Table 13:

[0179] Table 13: Examples of polypeptide derivative tablets prepared in this application

[0180] The preparation method of the polypeptide derivative tablet containing fatty acid side chains is as follows: the polypeptide derivative and PNAC are sieved, mixed evenly with auxiliary materials, and directly tableted.

[0181] Example 9: Study on the Pharmacokinetic (PK) Properties of Fatty Acid Side Chain-Containing Polypeptide Derivative Tablets

[0182] Male Beagle dogs (9-12 kg) aged 10-15 months were orally administered the oral tablets prepared in Example 4 once daily for 5 consecutive days. The dose of the fatty acid side chain-containing polypeptide derivatives (iePD065, PD187, PD183) administered was 7 mg / dog (n=5). The date of the first oral administration was designated as Day 1, and the date of the last oral administration was designated as Day 5. On Day 1, whole blood was collected from the animals before administration (-10 min) and 2, 4, and 8 hours after administration, and plasma was prepared (sodium heparin was used as the anticoagulant). On Days 2-4, whole blood was collected from the animals before administration (-10 min) and 2, 4 hours after administration, and plasma was prepared (sodium heparin was used as the anticoagulant). On Day 5, whole blood was collected from the animals before administration (-10 min) and 2, 4, 8, 24, 48, and 72 hours after administration, and plasma was prepared (sodium heparin was used as the anticoagulant). Plasma was stored at -80°C and used for subsequent analysis. Plasma drug content was analyzed using LC-MS / MS (Waters ACQUITY I Class Premier UPLC tandem with Sciex 6500+QQQ). Experimental data were plotted using GraphPad Prism 9.3.1. The plasma concentrations of the three peptide derivatives (iePD065, PD187, and PD183) measured at the indicated time points after administration of the three peptide derivative tablets are shown in Figure 6.

[0183] The charge-to-mass ratio is the ratio of the charge of a charged particle to its mass. The ion-to-charge-to-mass ratio used for PD065 is 1102.9 / 1074.5, the ion-to-charge-to-mass ratio used for PD187 is 1153 / 1120.9, and the ion-to-charge-to-mass ratio used for PD183 is 945.6 / 919.8.

[0184] The results shown in Figure 6 show that although compounds PD187 and PD183 both have superior weight loss efficacy, under the same delivery environment, their oral availability was not improved compared to the tablet group containing compound PD065; surprisingly, the compound PD183 molecule showed a special synergistic effect in the tablet of the delivery agent PNAC, demonstrating extremely high oral bioavailability.

[0185] Although the embodiments of the present application are described above, the present application is not limited to the above-mentioned specific embodiments and application fields. The above-mentioned specific embodiments are merely illustrative and instructive, and not restrictive. A person of ordinary skill in the art, under the guidance of this specification and without departing from the scope of protection of the claims of this application, can also make many forms, all of which fall within the scope of protection of this application.

Claims

1. An amylin polypeptide analog or its derivative and a pharmaceutically acceptable salt thereof, wherein: Contains the amino acid sequence represented by formula (I): X1CNTATCATQRLAX 14 FLX 17 HX 19 X 20 X 21 X 22 X 23 X 24 X 25 ILX 28 X 29 TNVGSX 35 TX 37 Formula (I), in, X1 is selected from K, D, Dab, Dap, E, H, Har, Orn, R or deleted, X 14 is selected from N, Aad, Dab, Dap, E or D, X 17 Selected from V, Orn or R, X 19 Select from S or K, X 20 Select from S or K, X 21 Selected from N or K, X 22 Selected from N or K, X 23 Selected from F, L or K, X 24 is selected from G, R, H, P, D, N, S, K, αK, Dap, Dab, Orn, Cit, Sar, Trx or AOC, X 25 Choose from A, K or P, X 28 Selected from S or P, X 29 Selected from S or P, X 35 Selected from N or G, X 37 Selected from Y, 3-Am-Pro, Aze, cis-Hyp, P, Pip, αMePro or trans-Hyp.

2. The polypeptide analog or derivative thereof and pharmaceutically acceptable salt thereof according to claim 1, wherein: Contains the amino acid sequence represented by formula (II): X1CNTATCATQRLAX 14 FLX 17 HSSNNX 23 X 24 X 25 ILX 28 X 29 TNVGSNTX 37 Formula (II) in, X1 is selected from K or R, X 14 Select from N or D, X 17 Selected from V or R, X 23 Select from F or L, X 24 Selected from G, R or K, X 25 Select from A or P, X 28 Selected from S or P, X 29 Selected from S or P, X 37 Selected from Y, P or trans-Hyp.

3. The polypeptide analog or derivative thereof and pharmaceutically acceptable salts thereof according to claim 2, wherein said X 14 It's D, X 17 It's R, X 23 It's L, X 25 It's P, X 28 It's P, X 29 It's P, X 37 It is P or trans-Hyp.

4. The polypeptide analog or derivative according to claim 3, or a pharmaceutically acceptable salt thereof, wherein X 24 is K or R; preferably, X1 is K.

5. The polypeptide analog or derivative thereof and pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising an amino acid sequence selected from SEQ ID NO. 2-104.

6. The polypeptide analog or polypeptide derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the polypeptide derivative or pharmaceutically acceptable salt thereof comprises 1 to 10 amino acid modifications. 7 . The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 6 , wherein the modification is located at the epsilon amino group at position 1.

8. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein the amino acid modification is the introduction of a functional group that can be used for coupling on the amino acid side chain. 9 . The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 8 , wherein the functional group that can be used for coupling comprises an extension portion and a linker connecting the extension portion and the modified amino acid.

10. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 9, wherein the extension portion is selected from or Where x is any integer from 4 to 38; Preferably, The extension portion is selected from: HOOC(CH2) 14 CO-, HOOC(CH2) 15 CO-, HOOC(CH2) 16 CO-, HOOC(CH2) 17 CO-, HOOC(CH2) 18 CO-, HOOC(CH2) 19 CO-, HOOC(CH2) 20 CO-, HOOC(CH2) 21 CO- and HOOC(CH2) 22 CO-.

11. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 9 or 10, wherein the linker is selected from: in, m is 0, 1, 2 or 3; n is 1, 2 or 3; s is any integer from 0 to 6; p is any integer from 1 to 8; Preferably, the linker is selected from: Wherein, m is 1, n is 1 or 2, and p is any integer from 1 to 5.

12. The polypeptide derivative according to claim 11 or a pharmaceutically acceptable salt thereof, selected from PD069, PD070, PD071, PD072, PD140, PD158, PD160, PD161, PD144, PD145, PD146, PD147 or PD187.

13. The polypeptide derivative according to claim 12 or a pharmaceutically acceptable salt thereof is 14. The polypeptide derivative according to claim 12 or a pharmaceutically acceptable salt thereof is 15. The polypeptide derivative according to claim 12 or a pharmaceutically acceptable salt thereof is 16. The polypeptide derivative according to claim 12 or a pharmaceutically acceptable salt thereof is 17. A method for preparing the polypeptide analogue or derivative thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16.

18. Use of the polypeptide analogue or derivative thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 in the preparation of a medicament for preventing or treating a disease. The use according to claim 18, wherein the disease is an amylin receptor-related disease.

20. The use according to claim 19, wherein the amylin receptor-related disease is selected from fat metabolism disorder, blood sugar metabolism disorder, cardiovascular disease, brain, mental or nervous system disease.

21. A method for treating and / or preventing a disease, comprising administering to a subject in need thereof the polypeptide analog or derivative thereof, and pharmaceutically acceptable salts, drugs or pharmaceutical compositions thereof according to any one of claims 1 to 16.

22. The method of claim 21, wherein the disease is selected from the group consisting of: lipodystrophy, dysglycemia, cardiovascular disease, brain, psychiatric or nervous system disease.

23. A pharmaceutical composition comprising the polypeptide analog or derivative thereof according to any one of claims 1 to 16 and a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition according to claim 23, further comprising one or more oral delivery agents; preferably, the oral delivery agent is N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC) salt; more preferably PNAC.

25. The pharmaceutical composition according to claim 23 or 24, further comprising one or more other pharmacologically active substances.

26. The pharmaceutical composition according to claim 25, wherein the pharmacologically active substance is selected from the group consisting of: weight regulators, anti-obesity agents, lipid metabolism regulators, blood sugar regulators, hypertension therapeutic agents, cardiovascular regulators, brain system regulators, mental system regulators, or nervous system regulators.

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