Amylin analogue, preparation and use thereof

Abstract

The present invention belongs to the field of pharmaceuticals, and specifically relates to an amylin analogue, a preparation method for the amylin analogue, and the use thereof. A provided insulin analogue can efficiently stimulate a variety of receptors including hCTR and hAMY3R. Animal experiments verify that the provided insulin analogue has a significant effect in reducing body weight. Accordingly, the provided amylin analogue can be used to treat or alleviate obesity and a series of diseases or disorders caused thereby, and can be used to treat a variety of metabolism-associated diseases.

Description

Amylin analogues, their preparation and uses

[0001] Cross-reference declaration

[0002] This disclosure claims priority to the following two Chinese applications: Chinese application No. 2024118443686, filed on December 13, 2024, entitled "Amylin Analogs, Preparation and Use Thereof", and Chinese application No. 2025105715028, filed on April 30, 2025, entitled "Amylin Analogs, Preparation and Use Thereof". The entire contents of both applications are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the pharmaceutical field, specifically relating to an amylin analogue, its preparation method, and its uses. Background Technology

[0004] Amylin is a member of the peptide hormone family, which includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin, and intermedin. Amylin is known to be associated with various metabolic diseases and disorders. Human amylin was first isolated from the islets of Langerhans in the pancreas of patients with type 2 diabetes; it is a major component of amyloid deposits in these patients, hence its name.

[0005] Natural human amylin is a 37-amino acid peptide with the following formula:

[0006] H-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2;

[0007] The N-terminal H- represents a hydrogen atom, corresponding to the free amino group present on the N-terminal amino acid residue [i.e., the lysine (K) residue at position 1 in the sequence shown above]; the C-terminal -NH2 indicates that the C-terminal carboxyl group is in amide form; and the parentheses () connected to the two cysteine ​​(C, Cys) residues at positions 2 and 7 indicate that there is an intramolecular disulfide bridge between the two Cys residues involved.

[0008] Amylin can be beneficial in the treatment of metabolic disorders such as diabetes and / or obesity. Amylin regulates gastric emptying and inhibits glucagon secretion and food intake, thereby modulating the rate of glucose release into the circulation; in a sense, amylin complements the effects of insulin. Compared to healthy adults, patients with type 1 diabetes lack circulating amylin, while patients with type 2 diabetes show reduced postprandial amylin concentrations.

[0009] WO 93 / 10146, WO2006 / 042745, WO91 / 07978, WO2013 / 156594, WO2012 / 168430, WO2012 / 168431, WO2012 / 168432, WO2015 / 040182, and WO2018 / 046719 disclose several amylin analogs, which exhibit improvements in one or more properties such as activity, stability, solubility, or half-life. However, their binding potency to specific receptors (e.g., hCT-R, hAMYR1, hAMYR2, or hAMYR3) is still expected to be further improved.

[0010] Furthermore, obesity is a leading risk factor for type 2 diabetes, which constitutes a growing and major global health problem. Diseases and disorders resulting from untreated diabetes include cardiovascular and peripheral artery disease, microvascular and macrovascular complications, stroke, and certain forms of cancer, particularly hematopoietic cancer. New treatments and agents are urgently needed to fundamentally alleviate the range of diseases and disorders caused by obesity. Summary of the Invention

[0011] The purpose of this disclosure is to provide an amylin analog that is highly potent against multiple amylin receptors, and a method for preparing the same. This highly potent insulin analog can be used to treat or alleviate obesity and a range of diseases or disorders it causes, and can also be used to treat a variety of metabolic-related diseases.

[0012] The first aspect of this disclosure provides an amylase analog having the structural formula R. 1 -ZR 2 ,in,

[0013] R 1 Selected from hydrogen, C 1-4 Acyl, benzoyl, C 1-4 An alkyl group or a group Y, said group Y being used to extend the half-life of the amylin analogue, said group Y being linked to Z via an optional linker;

[0014] R 2 Selected from OH or NHR 3 , where R 3 Is it hydrogen or C? 1-3 alkyl;

[0015] Z has the amino acid sequence shown in formula (Ⅰ):

[0016] Arg-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-Glu-Arg-X 12-Ala-Aad-X 15 -Leu-Gln-X 18 -X 19 -X 20 -Phe-Sar-Ala-X 24 -Leu-Ser-Ser-Thr-Glu-X 30 -Gly-Ser-Asn-Thr-Hyp(Ⅰ)

[0017] X2 is an Asp;

[0018] X3 is selected from Gly and Asn;

[0019] X7 is Lys;

[0020] X 12 Selected from Leu and αMeL;

[0021] X 15 Selected from Phe and αMeF;

[0022] X 18 Selected from Arg and His;

[0023] X 19 Selected from Ser and Tyr;

[0024] X 20 Selected from Ser and Arg;

[0025] X 24 Selected from Ile (Me), Pro and Sar;

[0026] X 30 Selected from Val and Thr;

[0027] The side chains of X2 and X7 are connected by lactam bridges;

[0028] Furthermore, the selection of amino acid residues does not include the following combinations: X2 is Asp, X3 is Gly, X7 is Lys, X... 12 For Leu, X 15 For Phe, X 18 For Arg, X 19 For Ser, X 20 For Ser, X 24 For Ile(Me) and X 30 It is Val.

[0029] In an optional implementation, the X 24 For Pro.

[0030] In an optional implementation, the X 24 For Sar.

[0031] In an optional implementation, X3 is Asn, or X 12 For αMeL, or, the X 15 For αMeF, or, the X 30 For Thr and X 19 For Ser.

[0032] In an optional implementation, the X 19 For Tyr, or, the X 18 His and the X 20 For Arg.

[0033] In an optional implementation, X2 is Asp, X7 is Lys, and X... 18 For Arg, X 19 For Ser and X 20 For Ser.

[0034] In an optional implementation, X 12 For αMeL, or, the X 15 It is αMeF.

[0035] In an optional embodiment, the amino acid sequence of Z is selected from any of the following:

[0036] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0037] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0038] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0039] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0040] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0041] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0042] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0043] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-αMeF-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0044] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-αMeL-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0045] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0046] Arg-Asp()-Asn-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0047] The parentheses “()” represent intramolecular lactam bridges formed between the side chains of the residues.

[0048] In an optional embodiment, the group Y includes a lipophilic substituent containing a hydrocarbon chain of 10 to 24 carbon atoms.

[0049] In an optional embodiment, the lipophilic substituent has a carboxylic acid group at the end of its hydrocarbon chain.

[0050] In an optional embodiment, the lipophilic substituent includes 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, or 19-carboxy-nonadecanoyl.

[0051] In an optional embodiment, the linker comprises the following residues: Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-Ala, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, or 8-amino-3,6-dioxaoctanoyl.

[0052] In an optional embodiment, the connector is selected from Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutyryl, 8-aminooctanoyl, or 8-amino-3,6-dioxaoctanoyl.

[0053] In an optional embodiment, the group Y is a 19-carboxy-nonadecanoyl group linked to Z via γ-Glu.

[0054] In an optional implementation, the R 2 It is NH2.

[0055] In an optional embodiment, the structure of the amylin analogue is selected from any of the following:

[0056] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 2);

[0057] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-A rg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 3);

[0058] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 4);

[0059] C 20diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2(compound);

[0060] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 6);

[0061] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 7);

[0062] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 8);

[0063] C 20diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-αMeF-Leu-Gl n-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 9);

[0064] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-αMeL-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 10);

[0065] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 11);

[0066] C 20 diacid-γGlu-Arg-Asp()-Asn-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 12);

[0067] The parentheses “()” represent intramolecular lactam bridges formed between the side chains of the residues.

[0068] A second aspect of this disclosure provides a salt or solvate of an amylin analogue as described in any of the foregoing embodiments.

[0069] A third aspect of this disclosure provides a composition comprising an amylin analogue as described in any of the foregoing embodiments, or a salt or solvate of an amylin analogue as described in the foregoing embodiments, and a pharmaceutically acceptable carrier.

[0070] The fourth aspect of this disclosure provides a method for preparing an amylin analog or a salt or solvate of an amylin analog as described in any of the foregoing embodiments, comprising synthesizing the amylin analog by a solid-phase or liquid-phase peptide synthesis method, optionally separating and / or purifying the final product, and optionally forming an amide bond between the side chains of X2 and X7.

[0071] The fifth aspect of this disclosure provides the use of amylin analogues described in any of the foregoing embodiments, or salts or solvates of amylin analogues described in the foregoing embodiments, or the use of compositions described in the foregoing embodiments in the preparation of medicaments for treating metabolic diseases.

[0072] In an optional implementation, the drug is used to treat, inhibit or reduce weight gain, or promote weight loss, or reduce excess weight.

[0073] In an optional implementation, the drug is used to treat: obesity, obesity-related inflammation, obesity-related gallbladder disease and obesity-induced respiratory problems, cartilage degeneration, osteoarthritis, or reproductive health complications of obesity or overweight.

[0074] In an optional embodiment, the drug is used to treat obesity; optionally, the obesity includes morbid obesity or preoperative obesity.

[0075] The amylin analogues or pharmaceutically acceptable salts or solvates are used for the prevention or treatment of: Alzheimer's disease, diabetes, hypertension, atherogenic dyslipidemia, hepatic steatosis, renal failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic cardiomyopathy, coronary artery disease, peripheral artery disease, or stroke, and combinations thereof.

[0076] The amylin analogues or pharmaceutically acceptable salts or solvates are used for the prevention or treatment of: type 1 diabetes, type 2 diabetes, prediabetes, fatty liver, atherosclerosis, diabetic cardiomyopathy and heart failure as complications of diabetes, and combinations thereof.

[0077] The amylin analogues or pharmaceutically acceptable salts or solvates are used for the prevention or treatment of: insulin resistance syndrome, impaired glucose tolerance, hyperglycemia, non-alcoholic fatty liver disease, and combinations thereof.

[0078] The amylin analogues or pharmaceutically acceptable salts or solvates are used to prevent or treat disease states associated with elevated blood glucose levels.

[0079] The amylin analogues or pharmaceutically acceptable salts or solvates are used for the prevention or treatment of non-alcoholic steatohepatitis.

[0080] The use of the aforementioned amylin analogue or pharmaceutically acceptable salt or solvate in the preparation of a medicament for reducing circulating LDL levels and / or increasing the HDL / LDL ratio.

[0081] The amylin analogue or pharmaceutically acceptable salt or solvate is administered as part of a combination therapy with antidiabetic agents, antiobesity agents, agents for the treatment of metabolic syndrome, antilipidemic agents, antihypertensive agents, proton pump inhibitors, or anti-inflammatory agents.

[0082] In an optional embodiment, the amylin analogue described in any of the foregoing embodiments, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject as part of a combination therapy along with an anti-obesity agent, wherein the anti-obesity agent is BGM0504 or a pharmaceutically acceptable salt or solvate thereof. Optionally, the weight ratio of BGM0504 to the amylin analogue is about 10:1 to 1:5; alternatively, it may be about 10:1 to 1:4, about 10:1 to 1:3, about 10:1 to 1:2, about 7:1 to 1:1.5, about 5:1 to 1:1.2, about 4:1 to 1:1.1, about 3:1 to 1:1, or about 2:1 to 1:1.

[0083] Optionally, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is about 0.3 to 16 mg, optionally about 0.3 to 10 mg, optionally about 0.6 to 4.8 mg, optionally about 0.6 to 2.4 mg; optionally, a dose selected from any one of about 0.3 mg, about 0.4 mg, about 0.6 mg, about 1 mg, about 1.2 mg, about 1.8 mg, about 2 mg, about 2.4 mg, about 2.5 mg, about 3 mg, about 3.6 mg, about 4 mg, about 4.8 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 9.6 mg, about 10 mg, about 14.4 mg, about 15 mg, or about 16 mg.

[0084] Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate may be administered to the subject once every 1 to 4 weeks or once every month, for example once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every month. Optionally, the duration of administration of the amylin analogue or its pharmaceutically acceptable salt or solvate may be 1 to 7 weeks, for example 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks.

[0085] Optionally, the dosage of BGM0504 or its pharmaceutically acceptable salts or solubilities is about 1 to 30 mg, optionally about 2.5 to 20 mg, or optionally about 5.0 to 15 mg. Optionally, the dosage is selected from any one of about 1 mg, about 1.25 mg, about 1.8 mg, about 2 mg, about 2.4 mg, about 2.5 mg, about 3 mg, about 3.6 mg, about 4 mg, about 4.8 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, or about 30 mg. Optionally, the frequency of administration of BGM0504 or its pharmaceutically acceptable salts or solubilities is either a single dose or once a week. Optionally, the duration of administration of BGM0504 or its pharmaceutically acceptable salts or solvates is 1 to 30 weeks, optionally 6 to 10 weeks or 26 to 30 weeks, for example 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks or 30 weeks.

[0086] In some implementations, the subjects are human subjects.

[0087] In some implementations, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is up to about 10 mg, for example up to about 9.5 mg, up to about 9 mg, up to about 8.5 mg, up to about 8 mg, up to about 7.5 mg, up to about 7 mg, up to about 6.5 mg, up to about 6 mg, up to about 5.5 mg, up to about 5 mg, up to about 4.5 mg, up to about 4 mg, up to about 3.5 mg, up to about 3 mg, up to about 2.5 mg, up to about 2 mg, up to about 1.5 mg, up to about 1 mg, up to about 0.5 mg, or up to about 0.25 mg.

[0088] In some embodiments, the subject is given about 0.04 mg to about 10 mg of any of the foregoing embodiments of the amylin analogue or its pharmaceutically acceptable salt or solvate, for example about 0.04 mg to about 7 mg, about 0.04 mg to about 6 mg, about 0.04 mg to about 4.4 mg, or about 0.04 mg to about 2.4 mg.

[0089] In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate described in any of the foregoing embodiments administered to the subject is about 0.6 mg to about 10 mg, about 0.6 mg to about 7 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 4.4 mg, or about 0.6 mg to about 2.4 mg.

[0090] In some embodiments, the amylin analogue or its pharmaceutically acceptable salt or solvate described in any of the foregoing embodiments is administered to the subject at a dose of about 0.7 mg to about 10 mg, about 0.7 mg to about 7 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 4.4 mg, or about 0.7 mg to about 2.4 mg.

[0091] In some embodiments, the dose of the islet amyloid polypeptide analogue provided by any of the foregoing embodiments administered to the subject is about 0.5 mg to about 10.0 mg, preferably about 0.6 mg to about 7.5 mg, preferably about 1.2 mg to about 7.5 mg, preferably about 1.2 mg to about 6.0 mg, preferably about 2.4 mg to about 6.0 mg, preferably about 2.4 mg to about 4.0 mg, preferably about 2.4 mg to about 3.5 mg.

[0092] In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate provided in any of the foregoing embodiments administered to the subject is about 10 mg, for example about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4.4 mg, about 4 mg, about 3.5 mg, about 3.4 mg, about 3 mg, about 2.5 mg, about 2.4 mg, about 2 mg, about 1.5 mg, about 1.4 mg, about 1 mg, about 0.5 mg, about 0.35 mg, about 0.25 mg, about 0.16 mg, about 0.08 mg, or about 0.04 mg.

[0093] In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate provided in any of the foregoing embodiments administered to the subject is about 0.0001 to about 1 mg / kg body weight, for example about 0.0005 to about 1 mg / kg body weight, about 0.001 to about 1 mg / kg body weight, about 0.01 to about 1 mg / kg body weight, about 0.1 to about 1 mg / kg body weight, about 0.2 to about 1 mg / kg body weight, about 0.3 to about 1 mg / kg body weight, about 0.4 to about 1 mg / kg body weight, or about 0.5 to about 1 mg / kg body weight.

[0094] In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate provided in any of the foregoing embodiments administered to the subject is about 0.0001 to about 0.5 mg / kg body weight, for example about 0.0005 to about 0.5 mg / kg body weight, about 0.001 to about 0.5 mg / kg body weight, about 0.01 to about 0.5 mg / kg body weight, about 0.1 to about 0.5 mg / kg body weight, about 0.2 to about 0.5 mg / kg body weight, about 0.3 to about 0.5 mg / kg body weight, or about 0.4 to about 0.5 mg / kg body weight.

[0095] In some embodiments, the subject is administered a dose of about 0.0001 to about 0.15 mg / kg body weight of an amylin analogue or a pharmaceutically acceptable salt or solvate thereof provided in any of the foregoing embodiments, such as about 0.0005 to about 0.15 mg / kg body weight, about 0.001 to about 0.15 mg / kg body weight, or about 0.01 to about 0.15 mg / kg body weight.

[0096] In some embodiments, the subject is administered a dose of about 0.0001 to about 0.1 mg / kg body weight of an amylin analogue or a pharmaceutically acceptable salt or solvate thereof provided in any of the foregoing embodiments, such as about 0.0005 to about 0.1 mg / kg body weight, about 0.001 to about 0.1 mg / kg body weight, or about 0.01 to about 0.1 mg / kg body weight.

[0097] In some embodiments, the amylin analogue or its pharmaceutically acceptable salt or solvate as described in any of the foregoing embodiments is administered to the subject at a dose of about 10 nmol / kg body weight to about 500 nmol / kg body weight, for example, about 10 to about 100 nmol / kg body weight, or about 10 to about 50 nmol / kg body weight. In some embodiments, the amylin analogue or its pharmaceutically acceptable salt or solvate as described in any of the foregoing embodiments is administered to the subject at a dose of about 10, 50, or 100 nmol / kg body weight.

[0098] In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate as described in any of the foregoing embodiments is not the same during each dosing period. In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate is increased during each consecutive dosing period. In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate is increased during each consecutive dosing period until the desired maximum dose is reached. Optionally, the desired maximum dose may be maintained for a given period of time (i.e., a dose stabilization period). In some embodiments, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate is the same during each dosing period.

[0099] In some implementations, the dose of BGM0504 or its pharmaceutically acceptable salts or solvates administered to the subject is up to about 25 mg, up to about 22.5 mg, up to about 20 mg, up to about 17.5 mg, up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, or up to about 1 mg.

[0100] In some implementations, the dose of BGM0504 or its pharmaceutically acceptable salts or solvates administered to the subject is about 1 mg to about 15 mg, about 2.5 mg to about 15 mg, about 5 mg to about 15 mg, about 7.5 mg to about 15 mg, about 10 mg to about 15 mg, or about 12.5 mg to about 15 mg.

[0101] In some implementations, the dose of BGM0504 or its pharmaceutically acceptable salts or solvates administered to the subject is about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, about 2.5 mg to about 10 mg, about 5 mg to about 10 mg, or about 7.5 mg to about 10 mg.

[0102] In some implementations, the dose of BGM0504 or its pharmaceutically acceptable salts or solvates administered to the subject is about 1 mg to about 5 mg, or about 2.5 mg to about 5 mg.

[0103] In some embodiments, the dose of BGM0504 or its pharmaceutically acceptable salts or solubilities administered to the subject is about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, about 5 mg, about 2.5 mg, or about 1 mg.

[0104] In some embodiments, BGM0504 or its pharmaceutically acceptable salts or solvates are administered to the subject at a dose of about 0.0001 to about 1 mg / kg body weight, such as about 0.0005 to about 1 mg / kg body weight, about 0.001 to about 1 mg / kg body weight, about 0.01 to about 1 mg / kg body weight, about 0.1 to about 1 mg / kg body weight, about 0.2 to about 1 mg / kg body weight, about 0.3 to about 1 mg / kg body weight, about 0.4 to about 1 mg / kg body weight, or about 0.5 to about 1 mg / kg body weight.

[0105] In some embodiments, BGM0504 or its pharmaceutically acceptable salts or solvates are administered to the subject at a dose of about 0.0001 to about 0.5 mg / kg body weight, such as about 0.0005 to about 0.5 mg / kg body weight, about 0.001 to about 0.5 mg / kg body weight, about 0.01 to about 0.5 mg / kg body weight, about 0.1 to about 0.5 mg / kg body weight, about 0.2 to about 0.5 mg / kg body weight, about 0.3 to about 0.5 mg / kg body weight, or about 0.4 to about 0.5 mg / kg body weight.

[0106] In some embodiments, BGM0504 or its pharmaceutically acceptable salts or solvates are administered to the subject at a dose of about 0.0001 to about 0.15 mg / kg body weight (e.g., about 0.0005 to about 0.15 mg / kg body weight, about 0.001 to about 0.15 mg / kg body weight, or about 0.01 to about 0.15 mg / kg body weight).

[0107] In some embodiments, BGM0504 or its pharmaceutically acceptable salts or solvates are administered to the subject at a dose of about 0.0001 to about 0.1 mg / kg body weight (e.g., about 0.0005 to about 0.1 mg / kg body weight, about 0.001 to about 0.1 mg / kg body weight, or about 0.01 to about 0.1 mg / kg body weight).

[0108] In some embodiments, BGM0504 or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 1 nmol / kg body weight to about 100 nmol / kg body weight, for example, about 1 to about 50 nmol / kg body weight, or about 1 to about 10 nmol / kg body weight. In some embodiments, BGM0504 or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 1, 5, or 10 nmol / kg body weight.

[0109] In some embodiments, BGM0504 or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 5 mg / mL to about 30 mg / mL. In some embodiments, BGM0504 or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL.

[0110] This disclosure covers, but is not limited to, the medical uses and treatment methods of simultaneously administering the amylin analogue or its pharmaceutically acceptable salt or solvate, as described in any of the foregoing embodiments, and BGM0504 or its pharmaceutically acceptable salt or solvate, to a subject. The aforementioned amylin analogue and BGM0504 may be administered to the subject at different time points and according to different dosage regimens (i.e., times). For example, the aforementioned amylin analogue may be administered daily, every two days, or weekly, while BGM0504 may be administered weekly. The aforementioned amylin analogue and BGM0504 may be administered at different times on the same day.

[0111] In some embodiments, the amylin analogue and BGM0504 described in any of the foregoing embodiments may be administered to the subject at different times or simultaneously. Therefore, in some embodiments, the amylin analogue and BGM0504 are administered to the subject at different times. In some embodiments, the amylin analogue and BGM0504 are administered to the subject simultaneously.

[0112] In some embodiments, the amylin analogue and BGM0504 are administered to the subject at different intervals. In some embodiments, the amylin analogue and BGM0504 are administered to the subject at the same interval.

[0113] The sixth aspect of this disclosure provides a pharmaceutical composition comprising an amylin analogue or a salt or solvate of an amylin analogue as described in any of the foregoing embodiments, and optionally an anti-obesity agent, an anti-diabetic agent, or a combination thereof.

[0114] In an optional embodiment, the anti-obesity agent is selected from one or more of orlistat, phentermine, bupropion, liraglutide, semaglutide, or tirzepatide, BGM0504, masidoside, and retaglutide; the anti-diabetic agent is selected from one or more of insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, dual receptor agonists of GIP and GLP-1, or SGLT-2 inhibitors.

[0115] In an optional embodiment, the amylin analogue or pharmaceutically acceptable salt or solvate is administered as part of a combination therapy with a dual receptor agonist of GIP and GLP-1. Preferably, the dual receptor agonist of GIP and GLP-1 is telposide and / or BGM0504.

[0116] The pharmaceutical composition comprises an amylin analogue or a salt or solvate of an amylin analogue as described in any of the foregoing embodiments, and a dual receptor agonist of GIP and GLP-1. Preferably, the dual receptor agonist of GIP and GLP-1 is telposide and / or BGM0504.

[0117] The seventh aspect of this disclosure provides a treatment method for a disease, wherein the disease includes a metabolic disease or obesity, and the treatment method includes administering to a subject an effective dose of an amylin analogue, a salt or solvate of an amylin analogue, or a pharmaceutical composition according to any of the foregoing embodiments.

[0118] The structure of BGM0504 is shown below:

[0119] The BGM0504 can be prepared according to the preparation method of BG128 in Example 1 disclosed in patent WO2022 / 199629A1.

[0120] The amylin analogues disclosed herein can efficiently activate multiple receptors, including hCTR and hAMY3R. Animal experiments have verified that the amylin analogues disclosed herein have significant effects in reducing body weight and suppressing appetite. Therefore, the amylin analogues disclosed herein can be used to treat or alleviate obesity and a range of related diseases or disorders, and can also be used to treat various metabolic-related diseases. Attached Figure Description

[0121] Figure 1 shows the mass spectrometry detection results of compound 1;

[0122] Figure 2 shows the mass spectrometry detection results of compound 2;

[0123] Figure 3 shows the mass spectrometry detection results of compound 3;

[0124] Figure 4 shows the mass spectrometry results of compound 4;

[0125] Figure 5 shows the mass spectrometry detection results of compound 5;

[0126] Figure 6 shows the mass spectrometry detection results of compound 6;

[0127] Figure 7 shows the mass spectrometry detection results of compound 7;

[0128] Figure 8 shows the mass spectrometry detection results of compound 8;

[0129] Figure 9 shows the mass spectrometry detection results of compound 9;

[0130] Figure 10 shows the mass spectrometry detection results of compound 10;

[0131] Figure 11 shows the mass spectrometry detection results of compound 11;

[0132] Figure 12 shows the mass spectrometry detection results of compound 12;

[0133] Figure 13 shows the trend of body weight change in some of the DIO rat groups in Example 4;

[0134] Figure 14 shows the trend of body weight change in some of the DIO rat groups in Example 4;

[0135] Figure 15 shows the trend of food intake changes in rats in each drug administration group during the DIO rat experiment in Example 4;

[0136] Figure 16 shows the trend of body weight change in rats in each drug administration group during the DIO rat experiment in Example 5;

[0137] Figure 17 shows the trend of weight change in rats in each drug administration group during the DIO rat experiment in Example 5.

[0138] Figure 18 shows the trend of cumulative food intake in each drug administration group of rats in the DIO rat experiment in Example 5. Detailed Implementation

[0139] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0140] I. Definition

[0141] Throughout this specification and the appended claims, unless the context otherwise requires, the word “comprise” and variations such as “comprises” and “comprising” are to be understood as implying inclusion of the stated member, integer, or step, or a group of members, integers, or steps, but not excluding any other member, integer, or step, or a group of members, integers, or steps. However, in some embodiments, such other members, integers, or steps, or groups of members, integers, or steps may be excluded, i.e., the subject matter is to include the stated member, integer, or step, or a group of members, integers, or steps. Unless otherwise indicated herein or clearly contradicted by the context, the terms “a / an” and “the” and similar references used in the context of describing this disclosure (especially in the context of the claims) are to be considered to cover both the singular and plural. The range of values ​​enumerated herein is intended only as a shorthand for individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were enumerated separately herein. Unless otherwise indicated herein or expressly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all instances or exemplary language (e.g., “such”) provided herein is intended only to better illustrate this disclosure and does not limit the scope of this disclosure as otherwise claimed. All language in this specification should not be construed as indicating that any unclaimed element is necessary for the practice of this disclosure.

[0142] Several documents are referenced in full throughout this specification. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) is incorporated herein by reference in its entirety. Nothing herein should be construed as an admission that this disclosure is not prior to any prior invention disclosed herein.

[0143] As used herein, the term "peptide" refers to a polymer of amino acids of any length, for example, comprising two or more, or three or more, or four or more, or six or more, or eight or more, or nine or more, or ten or more, or thirteen or more, or sixteen or more, or twenty-one or more amino acids covalently linked by peptide bonds. A peptide may, for example, consist of up to 100 amino acids. The term "polypeptide" refers to a large peptide, preferably a peptide having more than 100 amino acid residues. The terms "oligopeptide," "oligomeric peptide," "polypeptide," and "protein" are used interchangeably herein.

[0144] As used herein, the term "amino acid" or "amino acid residue" refers to naturally occurring amino acids, non-natural amino acids that function in a similar manner to naturally occurring amino acids, amino acid analogs, and amino acid mimics, all of which are stereoisomers if their structure allows for their D and L stereoisomer forms. Amino acids are referred to herein by their names, their well-known three-letter symbols, or the single-letter symbols recommended by the IUPAC-IUB Committee on Biochemistry Nomenclature.

[0145] When used in conjunction with amino acids, the term “naturally occurring” refers to the 20 common amino acids (i.e., alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y)), as well as selenocysteine, pyrrolidone (PYL), and pyrrolidone-carboxylysine (PCL).

[0146] As used herein, the term "non-natural amino acid" means an amino acid that is not encoded by the genetic code of any organism or that has not been found in any organism. It can be, for example, a purely synthetic compound. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azetidine carboxylicacid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, and N-ethylglycine. N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesin, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthylalanine, valine, leucine, ornithine, D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline.

[0147] As used herein, the term "amino acid analogue" refers to a compound having the same basic chemical structure as a naturally occurring amino acid. Amino acid analogues include natural and non-natural amino acids that have been reversibly or irreversibly chemically blocked, or whose C-terminal carboxyl group, N-terminal amino group, and / or side-chain functional groups have been chemically modified. Such analogues include, but are not limited to, methionine sulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine ​​sulfoxide, S-(carboxymethyl)-cysteine ​​sulfone, aspartic acid-(β-methyl ester), N-ethylglycine, alanine carboxamide, homoserine, ortholeucine, and methionine methylsulfonium.

[0148] As used herein, the term "amino acid analogue" refers to a chemical compound that has a structure different from the general chemical structure of amino acids, but functions in a manner similar to that of naturally occurring amino acids.

[0149] In some embodiments, the variant includes at least one additional amino acid at its N-terminus. In one embodiment, the at least one additional amino acid is selected from naturally occurring amino acids other than proline, non-natural amino acids, amino acid analogs, and amino acid mimics. In one embodiment, the at least one additional amino acid is selected from G, A, N, and C. In a particular embodiment, the at least one additional amino acid is G.

[0150] The following table shows some of the amino acids, amino acid analogs, protected forms of Fmoc solid-phase synthesis, and their abbreviations involved in this disclosure:

[0151] drugs or combinations of drugs

[0152] The term "pharmaceutically acceptable" refers to those compounds, materials, combinations, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0153] The drugs or drug combinations disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising conventional, non-toxic, pharmaceutically acceptable carriers.

[0154] The term "treatment" includes the suppression, relief, prevention, or elimination of one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or reduce one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. Precise dosages will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0155] As used in the context of this disclosure, the term "prevention" and its grammatical variations (e.g., "prevented," "preventing," "prevent") refer to measures taken to prevent or inhibit the occurrence of a symptom, disease, or disorder, or to alter its pathological condition. Therefore, "prevention" can refer to prevention or preventative measures. For the purposes of this disclosure, favorable or desired clinical outcomes include, but are not limited to, prevention or mitigation of the symptoms, progression, or occurrence of a disease, whether detectable or undetectable. Therefore, the object requiring "prevention" (e.g., a person) can be an object that does not suffer from the disease or disorder involved. Thus, the term "prevention" includes suppressing or mitigating the onset of a disease relative to the absence of treatment, and does not necessarily imply permanent prevention of the associated disease, disorder, or symptom.

[0156] The term "about" refers to a range of acceptable error for a particular value as determined by those skilled in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or implementation, unless otherwise expressly stated in the embodiments or elsewhere in the specification, "about" means within one standard deviation, or up to 5% (whichever is greater), according to convention in the art.

[0157] As used herein, the term "medicinal salt" is intended to mean a salt that is harmless to a patient or subject when administered to them. It may suitably be a salt selected, for example, from acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrates, and acetates. Examples of basic salts include salts in which the cation is selected from: alkali metal cations (e.g., sodium or potassium ions), alkaline earth metal cations (e.g., calcium or magnesium ions), and substituted ammonium ions, such as N(R) ions. 1 (R) 2 (R) 3 (R) 4 )+ Type Ions, where R 1 R 2 R 3 and R 4 Typically, C represents hydrogen independently, optionally substituted. 1-6 Alkyl or optionally substituted C 2-6 Alkenyl. Related C 1-6 Examples of alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl. Possibly related C 2-6 Examples of alkenyl groups include vinyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically usable salts are described in Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66: 2 (1977).

[0158] In the context of this disclosure, the term "solvate" refers to a stoichiometric complex formed between a solute (in this case, a peptide or its pharmaceutically acceptable salt according to this disclosure) and a solvent. In this respect, the solvent may be, for example, water, ethanol, or other pharmaceutically acceptable (typically small molecule) organic substances, such as, but not limited to, acetic acid or lactic acid. When the solvent involved is water, such sovates are generally referred to as hydrates.

[0159] A table comparing the full English abbreviations with their Chinese meanings:

[0160] II. Detailed Implementation

[0161] The first aspect of this disclosure provides an amylase analog having the structural formula R. 1 -ZR 2 ,in,

[0162] R 1 Selected from hydrogen, C 1-4 Acyl, benzoyl, C 1-4 An alkyl group or a group Y, said group Y being used to extend the half-life of the amylin analogue, said group Y being linked to Z via an optional linker;

[0163] R 2 Selected from OH or NHR 3 , where R 3 Is it hydrogen or C? 1-3 alkyl;

[0164] Z has the amino acid sequence shown in formula (Ⅰ):

[0165] Arg-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-Glu-Arg-X 12 -Ala-Aad-X 15-Leu-Gln-X 18 -X 19 -X 20 -Phe-Sar-Ala-X 24 -Leu-Ser-Ser-Thr-Glu-X 30 -Gly-Ser-Asn-Thr-Hyp(Ⅰ)

[0166] in,

[0167] X2 is an Asp;

[0168] X3 is selected from Gly and Asn;

[0169] X7 is Lys;

[0170] X 12 Selected from Leu and αMeL;

[0171] X 15 Selected from Phe and αMeF;

[0172] X 18 Selected from Arg and His;

[0173] X 19 Selected from Ser and Tyr;

[0174] X 20 Selected from Ser and Arg;

[0175] X 24 Selected from Ile (Me), Pro and Sar;

[0176] X 30 Selected from Val and Thr;

[0177] The side chains of X2 and X7 are connected by lactam bridges;

[0178] Furthermore, the selection of amino acid residues does not include the following combinations: X2 is Asp, X3 is Gly, X7 is Lys, X... 12 For Leu, X 15 For Phe, X 18 For Arg, X 19 For Ser, X 20 For Ser, X 24 For Ile(Me) and X 30 It is Val.

[0179] In an optional implementation, the X 24 For Pro.

[0180] In an optional implementation, the X 24 For Sar.

[0181] In an optional implementation, X3 is Asn, or X 12 For αMeL, or, the X 15 For αMeF, or, the X 30 For Thr and X 19 For Ser.

[0182] Furthermore, when X 24 When it is Pro, X3 can be Asn, and / or X 12 It can be αMeL, and / or, X 15 It can be αMeF, and / or, X 30 It can be Thr. Furthermore, X2 can be Asp, X7 can be Lys, and X... 18 It can be Arg, X 19 It can be Ser and X 20 It can be Ser.

[0183] For example, the selection of each amino acid residue can be any of the following combinations:

[0184] (a)X 24 For Pro, X3 can be Asn, X2 can be Asp, X7 can be Lys, and X... 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 12 For Leu, X 15 For Phe, X 30 It is Val.

[0185] (b)X 24 For Pro, X 12 X2 can be αMeL, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 15 For Phe, X 30 It is Val.

[0186] (c)X 24 For Pro, X 15 X2 can be αMeF, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 12 For Leu, X 30 It is Val.

[0187] (d)X 24 For Pro, X 30 X2 can be Thr, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 12 For Leu, X 15 For Phe.

[0188] Furthermore, when X 24 When X is Sar, X3 can be Asn, and / or X 12 It can be αMeL, and / or, X 15 It can be αMeF, and / or, X 30 It can be Thr. Furthermore, X2 can be Asp, X7 can be Lys, and X... 18 It can be Arg, X 19 It can be Ser and X 20 It can be Ser.

[0189] For example, the selection of each amino acid residue can be any of the following combinations:

[0190] (a)X 24 For Sar, X3 can be Asn, X2 can be Asp, X7 can be Lys, and X... 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 12 For Leu, X 15 For Phe, X 30 It is Val.

[0191] (b)X 24 For Sar, X 12 X2 can be αMeL, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 15 For Phe, X 30 It is Val.

[0192] (c)X 24 For Sar, X 15 X2 can be αMeF, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X20 It can be Ser, X 12 For Leu, X 30 It is Val.

[0193] (d)X 24 For Sar, X 30 X2 can be Thr, X3 can be Gly, X2 can be Asp, X7 can be Lys, X 18 It can be Arg, X 19 It can be Ser, X 20 It can be Ser, X 12 For Leu, X 15 For Phe.

[0194] In an optional implementation, the X 19 For Tyr, or, the X 18 His and the X 20 For Arg.

[0195] In an optional implementation, X2 is Asp, X7 is Lys, and X... 18 For Arg, X 19 For Ser and X 20 For Ser.

[0196] In an optional implementation, X 12 For αMeL, or, the X 15 It is αMeF.

[0197] In an optional embodiment, the amino acid sequence of Z is selected from any of the following:

[0198] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0199] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0200] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0201] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0202] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0203] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0204] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0205] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-αMeF-Leu-Gln-Arg-Ser-Ser-Phe-Sa r-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0206] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-αMeL-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sa r-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0207] Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp;

[0208] Arg-Asp()-Asn-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp;

[0209] The parentheses “()” represent intramolecular lactam bridges formed between the side chains of the residues.

[0210] In an optional embodiment, the group Y includes lipophilic substituents containing 10 to 24 carbon atom hydrocarbon chains, including but not limited to lipophilic substituents with 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 carbon atom hydrocarbon chains.

[0211] In an optional embodiment, the lipophilic substituent has a carboxylic acid group at the end of its hydrocarbon chain.

[0212] In an optional embodiment, the lipophilic substituent includes 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, or 19-carboxy-nonadecanoyl.

[0213] In an optional embodiment, the linker comprises the following residues: Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-Ala, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, or 8-amino-3,6-dioxaoctanoyl.

[0214] In an optional embodiment, the connector is selected from Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutyryl, 8-aminooctanoyl, or 8-amino-3,6-dioxaoctanoyl.

[0215] In an optional embodiment, the group Y is a 19-carboxy-nonadecanoyl group linked to Z via γ-Glu. The skeletal nitrogen of the Arg residue at position X1 in the amino acid sequence of Z is covalently linked to the side chain carboxyl group of the γ-Glu moiety via an amide bond.

[0216] In an optional implementation, the R 2 It is NH2.

[0217] Taking compound 10 as an example, the sequence of compound 10 is as follows:

[0218] C20 diacid-γGlu-RD()GTATK()ATER-αMeL-A-Aad-FLQRSSF-Sar-A-Sar-LSSTEVGSNT-Hyp-NH2,

[0219] The corresponding structure is:

[0220] In an optional embodiment, the structure of the amylin analogue is selected from any of the following:

[0221] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 2);

[0222] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-A rg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 3);

[0223] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 4);

[0224] C 20diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2(compound);

[0225] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 6);

[0226] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 7);

[0227] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 8);

[0228] C 20diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-αMeF-Leu-Gl n-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 9);

[0229] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-αMeL-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 10);

[0230] C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 11);

[0231] C 20 diacid-γGlu-Arg-Asp()-Asn-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln -Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 12);

[0232] The parentheses “()” represent intramolecular lactam bridges formed between the side chains of the residues.

[0233] A second aspect of this disclosure provides a salt or solvate of an amylin analogue as described in any of the foregoing embodiments.

[0234] A third aspect of this disclosure provides a composition comprising an amylin analogue as described in any of the foregoing embodiments, or a salt or solvate of an amylin analogue as described in the foregoing embodiments, and a pharmaceutically acceptable carrier.

[0235] The fourth aspect of this disclosure provides a method for preparing an amylin analog or a salt or solvate of an amylin analog as described in any of the foregoing embodiments, comprising synthesizing the amylin analog by a solid-phase or liquid-phase peptide synthesis method, optionally separating and / or purifying the final product, and optionally forming an amide bond between the side chains of X2 and X7.

[0236] The solid-phase peptide synthesis method includes, but is not limited to, the Fmoc solid-phase synthesis method. The Fmoc solid-phase synthesis method comprises using Fmoc-Rink MBHA Amide resin to synthesize the target compound in a solid-phase manner. Fmoc is removed using 20% ​​piperidine / DMF. Oxyma / DIC is used as the coupling reagent, DMF as the reaction solvent, and the reaction is monitored using ninhydrin detection. The amino acids in the main chain are coupled sequentially. After the main chain is complete, the side-chain protecting groups -Alloc (lysine) and -OAll (aspartic acid) are removed using tetrakis(triphenylphosphine)palladium / phenylsilane / DCM solution, followed by cyclization using HCTU / DIEA. After solid-phase synthesis, the synthesized product is cleaved by 95% TFA / 2.5% water / 2.5% TIS, precipitated by cold TBME, purified by HPLC, and lyophilized to obtain the target compound.

[0237] The fifth aspect of this disclosure provides the use of amylin analogues described in any of the foregoing embodiments, or salts or solvates of amylin analogues described in the foregoing embodiments, or the use of compositions described in the foregoing embodiments in the preparation of medicaments for treating metabolic diseases.

[0238] In an optional implementation, the drug is used to treat, inhibit or reduce weight gain, or promote weight loss, or reduce excess weight.

[0239] In an optional embodiment, the drug is used to treat obesity; optionally, the obesity includes morbid obesity or preoperative obesity.

[0240] In an optional embodiment, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered to the subject once every 1 to 4 weeks or once every month, for example once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every month. Optionally, the duration of administration of the amylin analogue or its pharmaceutically acceptable salt or solvate is 1 to 7 weeks, for example 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks.

[0241] In optional embodiments, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once a week for a duration of 1, 2, 3, 4, 5, 6, or 7 weeks; optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 2 weeks for a duration of 2, 4, or 6 weeks; optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 3 weeks for a duration of 3 or 6 weeks; optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 4 weeks for a duration of 4 weeks.

[0242] The sixth aspect of this disclosure provides a pharmaceutical composition comprising an amylin analogue or a salt or solvate of an amylin analogue as described in any of the foregoing embodiments, and optionally an anti-obesity agent, an anti-diabetic agent, or a combination thereof.

[0243] The amylin analogue or pharmaceutically acceptable salt or solvate is administered as part of a combination therapy with antidiabetic agents, antiobesity agents, agents for the treatment of metabolic syndrome, antilipidemic agents, antihypertensive agents, proton pump inhibitors, or anti-inflammatory agents.

[0244] In an optional embodiment, the anti-obesity agent is selected from one or more of orlistat, phentermine, bupropion, liraglutide, semaglutide, tirzepatide, and BGM0504; the anti-diabetic agent is selected from one or more of insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, dual receptor agonists of GIP and GLP-1, or SGLT-2 inhibitors.

[0245] Optional combinations include, but are not limited to, the amylin analogues provided in this disclosure and orlistat, the amylin analogues provided in this disclosure and phentermine, the amylin analogues provided in this disclosure and bupropion, the amylin analogues provided in this disclosure and liraglutide, the amylin analogues provided in this disclosure and smegglutide, the amylin analogues provided in this disclosure and telposide, the amylin analogues provided in this disclosure and BGM0504, the amylin analogues provided in this disclosure and insulin, the amylin analogues provided in this disclosure and sulfonylurea reagents, the amylin analogues provided in this disclosure and biguanide reagents, and the amylin analogues provided in this disclosure and α-glucose. Amylinase inhibitors, amylin analogs and thiazolidinediones provided in this disclosure, amylin analogs and DPP-4 inhibitors provided in this disclosure, amylin analogs and GLP-1 receptor agonists provided in this disclosure, amylin analogs and dual receptor agonists of GIP and GLP-1 provided in this disclosure, amylin analogs and SGLT-2 inhibitors provided in this disclosure, amylin analogs, semaglutide and liraglutide provided in this disclosure, amylin analogs, SGLT-2 inhibitors and GLP-1 receptor agonists provided in this disclosure, amylin analogs, semaglutide and GLP-1 receptor agonists provided in this disclosure.

[0246] The seventh aspect of this disclosure provides a treatment method for a disease, wherein the disease includes a metabolic disease or obesity, and the treatment method includes administering to a subject an effective dose of an amylin analogue, a salt or solvate of an amylin analogue, or a pharmaceutical composition according to any of the foregoing embodiments.

[0247] Natural amylin is known to have poor stability in aqueous solution and readily aggregates to form fibrils. Reports have included methods to reduce this fibrillation tendency by incorporating N-methylated residues or introducing one or more amino acid substitutions. Notably, natural amylin and amylin analogs such as pramlinin contain a disulfide bond formed by cysteine ​​residues between the second and seventh positions. The presence of this bond makes natural amylin or its analogs highly susceptible to dimerization or oligomerization, for example, through disulfide bond exchange reactions between amylin molecules. Therefore, modifying this disulfide bond is an effective way to improve the stability of amylin. However, it has been verified that this disulfide bond is highly correlated with the activity of amylin; disrupting the disulfide bond significantly reduces the potency of amylin. For example, WO99 / 34764 showed that replacing the disulfide bridge with an intramolecular lactam bridge in the sequence of natural human amylin resulted in an amylin analog (2,7-cyclo-[2Asp,7Lys]-h-amyl) with significantly lower potency than wild-type and many other amylin analogs.

[0248] While retaining the intramolecular lactam bridge to replace the disulfide bridge, WO2018 / 046719 made various modifications to the amino acid residues of natural amylin, so that the activity of amylin analogs against hCT-R, hAMY1R, hAMY2R and / or hAMY3R receptors was not reduced. At the same time, as supplements or substitutes, they can exhibit excellent chemical stability and fibrillation resistance, especially but not limited to the neutral pH range. Therefore, this disclosure confirms that modifying amylin by altering or replacing amino acid residues is no longer sufficient to further improve the potency of amylin analogs by replacing disulfide bridges to improve stability and fibrillation resistance.

[0249] The amylin analogs disclosed herein, by using amino acid derivatives to replace natural amino acid residues and / or by methylating specific amino acid residues, achieve a technical effect of further improving the efficacy of amylin analogs while retaining intramolecular lactam bridges by replacing disulfide bridges, especially for hCT-R and / or hAMY3R receptors. Furthermore, animal experiments have verified that, compared with existing amylin analogs, the amylin analogs disclosed herein have a more significant weight loss effect in rats.

[0250] III. Examples

[0251] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0252] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0253] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0254] This disclosure lists the compounds shown in the table below as examples of amylin analogues, where parentheses “()” indicate intramolecular lactam bridges formed between the side chains of residues.

[0255] Table 1. Peptide sequences of compounds 1 to 12

[0256] Example 1: Synthesis of Compound 1 (Positive Control: Petrelintide) - Compound 12

[0257] Using the Fmoc protection method, the following protected amino acids were sequentially linked to Rink MBHA Amide resin via solid-phase organic synthesis:

[0258] Fmoc-Hyp(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Gly-OH, Fmoc-Va l-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Leu-OH, F moc-Ile(Me)-OH, Fmoc-Ala-OH, Fmoc-Sar-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fm oc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Aad(OtBu)-OH, Fmoc-Ala-OH, F moc-Leu-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ala-OH, Fmoc-Lys(All oc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ala-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Asp(OAll)-OH, Fmoc -Arg(Pbf)-OH, Fmoc-Glu-OtBu, and tert-butyl eicosanoate were added, followed by the removal of the lysine side-chain protecting group -Alloc and the aspartic acid side-chain protecting group -OAll by adding tetra(triphenylphosphine)palladium (0.1 eq) / phenylsilane (24 eq) / DCM. The mixture was washed with DCM and DMF, and tested positive for ninhydrin. Then, HCTU / DIEA was added for cyclization. After the ninhydrin reaction was considered complete, the mixture was washed with DMF and DCM to obtain the fully protected resin of compound 1. The resin was then cleaved using 95% TFA / 2.5% water / 2.5% TIS, followed by precipitation with ice-cold TBME and washing. The crude product was purified by reversed-phase HPLC and freeze-dried to obtain the target compound 1.

[0259] Compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 were synthesized using the same solid-phase synthesis and purification methods. Mass spectrometry analysis of compounds 1–12 is shown in Figures 1–12. The molecular weights and characteristic ion peaks of each compound are shown in the table below.

[0260] Table 2 Molecular mass and molecular ion peak of compounds 1 to 12

[0261] Example 2: Determination of the agonistic activity of compounds 1-12 with hCTR and hAMY3R

[0262] To evaluate the in vitro activity of the amylin analogs provided in this disclosure, the receptor agonist activity of the amylin analogs provided in this disclosure was detected using HEK293 cell lines expressing hAMY3R C11 (WuXi AppTec Co., Ltd.) and HEK293 cell lines expressing hCTR C5.

[0263] hAMY3R is a heterooligomer of the two genes formed when calcitonin receptor and RAMP3 are expressed in the same cell. The hCTR cell line expresses only the recombinant human calcitonin receptor gene. The amylin analogs provided in this disclosure can activate hCTR or hAMY3R and induce cAMP formation; therefore, the receptor agonistic potency of the amylin analogs provided in this disclosure can be measured using a cAMP assay kit.

[0264] The detection methods include:

[0265] (1) Prepare detection buffer: Prepare HBSS buffer (Invitrogen, Cat#14025) containing 20mM HEPES (Invitrogen, Cat#15630-106) and 500μM IBMX (Sigma, Cat#15879) at pH 7.4.

[0266] (2) Compound dilution: The reference amylin (New Research Bomei, Cat#Y-DS-6697), reference calcitonin (ACMEC, Cat#C19300-1MG), and compounds 1 to 12 synthesized in Example 1 were diluted using the Bravo platform.

[0267] The reference amylin (NewBioMed, Cat#Y-DS-6697) was serially diluted 4-fold using DMSO (total of 10 spots, starting concentration 100 nM). 50 nL of the diluted reference amylin was added to the test plate, sonicated, and then 5 μL of test buffer was added. The plate was then centrifuged at 1000 rpm for 10 s to obtain the reference plate.

[0268] The reference calcitonin (ACMEC, Cat#C19300-1MG) was serially diluted 4-fold using DMSO (total 10 spots, starting concentration 200 nM). 50 nL of the diluted reference calcitonin was added to the test plate, sonicated, and then 5 μL of test buffer was added. The plate was centrifuged at 1000 rpm for 10 s to obtain the reference plate.

[0269] Compounds 1 to 12 synthesized in Example 1 were serially diluted 4-fold (10 spots in total, starting concentration 200 nM) using detection buffer. 5 μL of each diluted compound was added to the detection plate, and the plates were obtained by centrifugation at 1000 rpm for 10 s.

[0270] (3) Thaw the cells, wash them with HBSS buffer, and then resuspend them in the prepared detection buffer.

[0271] (4) Add 5 μL of cell solution containing 20,000 cells to each well of the reference plate and the compound plate, shake for 20 s, centrifuge at 1000 rpm for 10 s, and incubate at 23°C for 1 h.

[0272] (5) Take 50 μL Eu 2+ Labeled antibody and 50 μL of cAMP tracer were dissolved in 5 mL of detection buffer to obtain diluted detection reagent. Then, 10 μL of detection reagent was added to each well of the reference plate and compound plate, vortexed for 20 s, centrifuged at 1000 rpm for 10 s, and incubated at 23°C for 1 h. Subsequently, detection was performed using a microplate reader, and the EC50 value and maximum activity (MaxActivity) of each compound were calculated using computer-aided curve analysis. The Eu... 2+ The labeled antibody and cAMP tracer were obtained from the cAMP HiRange Detection Kit, VKEY-Bio (Cat#-A1CM0006L). For detailed experimental methods, please refer to the instruction manual of this kit.

[0273] Table 3 Results of the assay of the agonist activities of compounds 1-12 with hCTR and hAMY3R

[0274] As can be seen from the data in Table 3, the in vitro activities of compounds 9 and 10 of the present invention on hCTR and hAMY3R receptors are significantly better than those of the positive control compound 1.

[0275] Example 3: Comparative pharmacokinetic (PK) analysis of compounds 1-12 in rats

[0276] Male Sprague Dawley rats were administered a single subcutaneous (sc) bolus of the compound at a dose of 1 mg / kg for each test peptide. Blood samples were collected from the tail vein before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 36 h, 48 h, 72 h, and 96 h after administration. The weight and food intake of each group of animals were recorded daily. After the last blood sampling, the rats were immediately euthanized by shock and cervical dislocation.

[0277] Rat body weight and food intake were recorded daily after administration. The delivery carrier for each test peptide was 10 mM PBS (pH 7.4). After precipitation with ethanol, plasma samples were analyzed by liquid chromatography-mass spectrometry (LC-MS / MS). Pharmacokinetic parameters were calculated using mean plasma concentrations. The results are shown in the table below:

[0278] Table 4. PK experiment results of compounds 1 to 13

[0279] Example 4: In vivo efficacy evaluation in a DIO rat obesity model

[0280] 4.1 Experimental Objective

[0281] The efficacy of the test samples, including compounds 1, 2, and 10, was evaluated using a rat obesity (DIO) model induced by a 60% high-fat diet.

[0282] Table 5 Compound Information

[0283] 4.2 Laboratory Animals

[0284] DIO model rats (male) were purchased from Speford (Suzhou) Biotechnology Co., Ltd. (Animal Production License No.: SCXK(Su)2022-0006) and housed in the SPF animal facility of Suzhou Leo Biotechnology Co., Ltd. (Animal Use License No.: SYXK(Su)2023-0024), fed a 60% high-fat diet (from arrival to the end of the experiment). Animals that were in good physical condition after at least 5 days of normal feeding were selected for this experiment upon veterinary examination. All procedures performed on the animals during the experiment must comply with the relevant SOP requirements for SD rat experiments conducted by Suzhou Leo Biotechnology Co., Ltd.

[0285] 4.3 Experimental Procedure

[0286] Animals were screened and randomly grouped according to their body weight and baseline body fat percentage. The experiment consisted of 5 groups. No significant difference in average body weight was observed among the groups. The animal dosing regimen is shown in Table 6. Dosing began on the day of grouping and continued every 3 days for a total of 4 doses, ending on day 13. All doses were administered via subcutaneous injection (sc) into the back. Group G received combined dosing, administered to both sides.

[0287] Table 6. Dosing regimen for DIO rats

[0288] 4.4 Index Measurement

[0289] Baseline body fat and lean body mass percentages were measured in each group of rats before administration, and endpoint body fat and lean body mass percentages were measured again after administration. Animal weight and food intake were recorded before each administration. Animals were euthanized (CO2) at the end of the experiment.

[0290] Table 7. In vivo efficacy evaluation of the DIO rat obesity model

[0291] As shown in Table 7 and Figures 13-14, the compound of this invention exhibited a higher rate of weight loss at the experimental endpoint compared to the control group compound. The compound provided by this invention demonstrates stable efficacy in rats. When the compound of this invention was used in combination with BGM0504, the weight loss rate in DIO model rats reached 22.7% after 13 days.

[0292] Table 8. Changes in animal food intake 13 days after drug administration.

[0293] As can be seen from Table 8 and Figure 15, the compounds provided in this disclosure have a significant effect on inhibiting feeding throughout the entire test period. The combination of the compounds of this invention with BGM0504 results in a better effect on inhibiting feeding than when used alone.

[0294] Example 5: Controlled experiment on the weight loss effect of combined treatment in DIO rats

[0295] 5.1 Laboratory Animals

[0296] DIO model rats (number: 36; sex: male; age: approximately 20 weeks) were purchased from Spiefol (Suzhou) Biotechnology Co., Ltd. (Animal Production License No.: SCXK(Su)2022-0006) and housed in the SPF animal facility of Suzhou Leo Biotechnology Co., Ltd. (Animal Use License No.: SYXK(Su)2023-0024). The temperature was 20–26℃, relative humidity 30%–70%, and lighting was 12 hours per hour (both light and dark). Animals had free access to water and were fed a 60% high-fat diet (from arrival to the end of the experiment). Animals that were in good physical condition after at least 5 days of normal feeding were selected for this experiment after veterinary examination. All procedures performed on the animals during the experiment must comply with the relevant SOP requirements for SD rat experiments conducted by Suzhou Leo Biotechnology Co., Ltd.

[0297] 5.2 Experimental Procedure

[0298] Animals were screened and randomly grouped according to body weight and baseline body fat percentage. A total of 6 groups were formed, and the animal administration regimens are shown in Table 9. The solvent was phosphate buffer solution at pH 1. Cagrilintide was prepared using acetate buffer at pH 4, and the remaining samples were prepared using phosphate buffer. Administration began on the day of grouping and continued every 3 days for a total of 10 administrations. All administrations were administered via subcutaneous injection (sc) in the back. Baseline body fat and lean body mass percentages were measured before administration, and endpoint body fat and lean body mass percentages were measured again the day after the last administration. Animal body weight and food intake were recorded before each administration.

[0299] Table 9. Dosing regimen for DIO rats

[0300] After the culture was completed, the changes in rat body weight and food intake were shown in Tables 10 and 11 and Figures 16-18. This example demonstrates that the amylin analogue (such as compound 10) of this disclosure, when used in combination with BGM0504, has a synergistic effect on weight loss and is significantly superior to the control group of Cagrilintide + Semaglutide and Amycretin.

[0301] Table 10. Average body weight and changes in rats in each group.

[0302] Table 11 Changes in food intake of rats in each group

[0303] Example 6: PK study of compound 10 injection in overweight or obese patients

[0304] This study enrolled 16 non-diabetic obese Chinese subjects, divided into two groups of 8 each. The two groups received subcutaneous injections of compound 10 (0.6 mg and 1.2 mg, respectively). Blood samples were collected at 0 h (±60 min) before administration on day 1, and at 4 h (±5 min), 8 h (±5 min), 12 h (±5 min), 24 h (±30 min), 36 h (±30 min), 48 h (±1 h), 72 h (±1 h), 96 h (±1 h), 120 h (±1 h), and 168 h (±1 h) after administration for pharmacokinetic (PK) parameter testing. Testing should also be performed upon early withdrawal / termination.

[0305] Pharmacokinetic results: In overweight / obese study subjects, after administration of 0.6 mg of compound 10 injection, the plasma concentration of compound 10 reached its peak at an average of approximately 30 hours, with an average half-life of approximately 363 hours after a single dose. The average C60 concentration of compound 10 after a single dose was [missing information]. max The mean AUC of compound 10 after a single dose was 71.4 ng / mL. 0-t It is 9888 h × ng / mL.

[0306] In overweight / obese study subjects, after administration of 1.2 mg of compound 10 injection, the plasma concentration of compound 10 peaked at an average of approximately 42 hours, with an average half-life of approximately 274 hours after a single dose. The average C10 concentration after a single dose was [missing information]. max The mean AUC of compound 10 after a single dose was 136.7 ng / mL. 0-t The value was 18734 h × ng / mL.

[0307] While specific embodiments of this disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of this disclosure. Therefore, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. An amylin analogue, a compound having the formula: ###0001### wherein, R 1 -Z-R 2 Z has an amino acid sequence of the formula (I): ###0002### wherein, R 1 selected from hydrogen, C 1-4 acyl, benzoyl, C 1-4 alkyl or a group Y, said group Y being for prolonging the half-life of the amylin analogue, said group Y being linked to Z through an optional linker; R 2 is selected from OH or NHR 3 wherein R 3 is hydrogen or C 1-3 alkyl; X2 is Asp; Arg-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-Glu-Arg-X 12 -Ala-Aad-X 15 -Leu-Gln-X 18 -X 19 -X 20 -Phe-Sar-Ala-X 24 -Leu-Ser-Ser-Thr-Glu-X 30 -Gly-Ser-Asn-Thr-Hyp (Ⅰ) X3 is selected from the group consisting of Gly and Asn; X7 is Lys; the side chains of said X2 and X7 are linked by a lactam bridge; the amino acid sequence of said Z is selected from any one of the following: Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp; wherein: - the amino acid sequence of Z is selected from any one of the following: Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thi-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyi-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thi-Glu-Thi-Gly-Ser-Asn-Thi-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-AIa-Thi-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyi-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thi-Glu-Thi-Gly-Ser-Asn-Thr-Hyp; X 12 selected from Leu and aMeL; X 15 selected from Phe and aMeF; X 18 selected from Arg and His; X 19 selected from Ser and Tyr; X 20 selected from Ser and Arg; X 24 is selected from He(Me), Pro and Sar; X 30 is selected from Val and Thr; ​ Also, the selection of amino acid residues does not include the following combinations: X2 is Asp, X3 is Gly, X7 is Lys, X 12 is Leu, X 15 is Phe, X 18 is Arg, X 19 is Ser, X 20 is Ser, X 24 is Ile(Me) and X 30 is Val.

2. The amylin analogue of claim 1, wherein, The X 24 is Pro.

3. The amylin analogue of claim 1, wherein, Said X 24 is S.

4. The amylin analogue according to any one of claims 1 to 3, wherein, X3 is Asn, or, X 12 is a MeL, or, X 15 is a MeF, or, X 30 is Thr and X 19 is Ser.

5. The amylin analogue according to any one of claims 1 to 4, wherein, X is Ser, or X is Tyr, or X is His, or X is Arg. 19 X is Ser, or X is Tyr, or X is His, or X is Arg. 18 X is Ser, or X is Tyr, or X is His, or X is Arg. 20 X is Ser, or X is Tyr 6. The amylin analogue of claim 4, wherein, X2 is Asp, X7 is Lys, X 18 is Arg, X 19 is Ser and X 20 is Ser.

7. The amylin analogue of claim 6, wherein, X 12 is aMeL, or, said X 15 is aMeF.

8. The amylin analogue of claim 1, wherein, ​ ​ ​ ​ ​ ​ ​ Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp; where the parentheses "()" indicate an intramolecular lactam bridge formed between the side chains of the residues.

9. The amylin analogue of any one of claims 1 to 8, wherein, The group Y includes a lipophilic substituent comprising a hydrocarbon chain of 10 to 24 carbon atoms.

10. The amylin analogue of claim 9, wherein, The hydrocarbon chain of the lipophilic substituent comprises a carboxylic acid group at its end.

11. The amylin analogue of claim 10, wherein, The lipophilic substituent comprises a 15-carboxy-pentadecanoyl group, a 17-carboxy-heptadecanoyl group, or, a 19-carboxy-nonadecanoyl group.

12. The amylin analogue according to any one of claims 8 to 11, wherein, The linker comprises the following residues: Gly, Pro, Ala, Val, Leu, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gin, Asn, a-Glu, y-Glu, e-Lys, Asp, b-Asp, Ser, Thr, Gaba, Aib, b-Ala, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7- aminohexanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl or 8-amino-3,6- dioxaoctanoyl.

13. The amylin analogue of claim 12, wherein, The linker is selected from the group consisting of Glu, y-Glu, e-Lys, b-Ala, 4- aminobutyryl, 8-aminooctanoyl and 8-amino-3,6-dioxaoctanoyl.

14. The amylin analogue of claim 13, wherein, The group Y is a 19-carboxy-nonadecanoyl group linked to Z via a y-Glu.

15. The amylin analogue of any one of claims 1 to 14, wherein, The R 2 is NH2.

16. The amylin analogue of any one of claims 1 to 15, wherein, The structure of the amylin analogue is selected from any one of the following: C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 2); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (Compound 3); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Pro-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 4); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (Compound 5); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Ile(Me)-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 6); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Tyr-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 7); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-His-Ser-Arg-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 8); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-αMeF-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (Compound 9); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-αMeL-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (Compound 10); C 20 diacid-γGlu-Arg-Asp()-Gly-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Thr-Glu-Thr-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 11); C 20 diacid-γGlu-Arg-Asp()-Asn-Thr-Ala-Thr-Lys()-Ala-Thr-Glu-Arg-Leu-Ala-Aad-Phe-Leu-Gln-Arg-Ser-Ser-Phe-Sar-Ala-Sar-Leu-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp-NH2 (compound 12); wherein the brackets "()" indicate an intramolecular lactam bridge formed between the side chains of the residues.

17. A salt or solvate of the amylin analogue according to any one of claims 1 to 16.

18. A composition comprising the amylin analogue according to any one of claims 1 to 16, or a salt or solvate of the amylin analogue according to claim 16, and a pharmaceutically acceptable carrier.

19. A method of preparing the amylin analogue according to any one of claims 1 to 16, or a salt or solvate of the amylin analogue according to claim 17, comprising synthesising the amylin analogue by solid phase or liquid phase peptide synthesis, optionally isolating and / or purifying the final product, and optionally forming an amide bond between the side chains of X2 and X7.

20. Use of the amylin analogue according to any one of claims 1 to 16, or a salt or solvate of the amylin analogue according to claim 17, or a composition according to claim 18, in the manufacture of a medicament for the treatment of a metabolic disease.

21. The use according to claim 20, wherein, The medicament is for the treatment, inhibition or reduction of weight gain, or the promotion of weight loss, or the reduction of excess body weight.

22. The use of claim 20, wherein, The medicament is for the treatment of obesity; Optionally, the obesity comprises morbid obesity or pre-surgical obesity.

23. The use according to claim 20, wherein the amylin analogue or pharmaceutically acceptable salt or solvate is administered as part of a combination therapy with an anti-diabetic agent, an anti-obesity agent, an agent for the treatment of metabolic syndrome, an anti-dyslipidaemic agent, an anti-hypertensive agent, a proton pump inhibitor or an anti-inflammatory agent.

24. The use according to claim 23, wherein, The anti-obesity agent is selected from one or more of Orlistat, Phentermine, bupropion, Liraglutide, Semaglutide, Tirzepatide, BGM0504, Maspedotide, Retalutide. The antidiabetic agent is selected from one or more of insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, dual receptor agonists of GIP and GLP-1, or SGLT-2 inhibitors.

25. A pharmaceutical composition comprising an amylin analogue as described in any one of claims 1-16 or a pharmaceutically acceptable salt or solvate of an amylin analogue as described in claim 16, and optionally an anti-obesity agent, an anti-diabetic agent, or a combination thereof.

26. A method of treatment of disease wherein, The disease includes metabolic diseases or obesity, and the treatment method includes administering to the subject an effective dose of an amylin analogue of any one of claims 1 to 16, or a salt or solvate of an amylin analogue of claim 17.

27. The use according to claim 23, wherein the amylin analogue or its pharmaceutically acceptable salt or solvate is administered as part of a combination therapy with an anti-obesity agent, said anti-obesity agent being BGM0504 or its pharmaceutically acceptable salt or solvate; Optionally, the weight ratio of BGM0504 or its pharmaceutically acceptable salt or solvate to the amylin analogue is about 10:1 to 1:5; alternatively, it can be about 10:1 to 1:4, about 10:1 to 1:3, about 10:1 to 1:2, about 7:1 to 1:1.5, about 5:1 to 1:1.2, about 4:1 to 1:1.1, about 3:1 to 1:1, or about 2:1 to 1:

1.

28. Use according to claim 23, 24 or 27, wherein, The dose of amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is approximately 0.3–16 mg; Optionally, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is about 0.3 to 10 mg; Optionally, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is about 0.6 to 4.8 mg; Optionally, the dose of the amylin analogue or its pharmaceutically acceptable salt or solvate administered to the subject is about 0.6 to 2.4 mg.

29. Use according to claim 23, 24, 27 or 28, wherein, The frequency of administration of the said amylin analogue or its pharmaceutically acceptable salt or solvate is (a) once every 1 to 4 weeks or (b) once every month; Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once a week. Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 2 weeks; Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 3 weeks; Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate is administered once every 4 weeks; Optionally, the amylin analogue or its pharmaceutically acceptable salt or solvate may be administered once a month.

30. The use of any one of claims 23, 24, 27-29, wherein, The duration of administration of the amylin analogue or its pharmaceutically acceptable salt or solvate is 1 to 7 weeks.

31. The use of claim 27, wherein, The dosage of BGM0504 or its pharmaceutically acceptable salts or solvates is approximately 1–30 mg; Optionally, the dosage of BGM0504 or its pharmaceutically acceptable salt or solvate is about 2.5 to 20 mg; Optionally, the dosage of the BGM0504 or its pharmaceutically acceptable salt or solvate is about 5.0-15 mg.

32. Use according to claim 27 or 31, wherein, The frequency of administration of the BGM0504 or its pharmaceutically acceptable salt or solvate includes single administration or once a week.

33. Use according to claim 27, 31 or 32, wherein, The duration of administration of the BGM0504 or its pharmaceutically acceptable salt or solvate is 1-30 weeks.

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