hAM15-52 analogues with enhanced potency against the amylin receptor (hAMY3R)

Abstract

The present invention relates to hAM15-52 analogues with enhanced amylin receptor (hAMY3R) potency (hAMY3R-EC50 ≤ 250 pM) and largely based on the human adrenomedullin fragment hAM15-52 sequence. The invention further relates to hAM15-52 analogues that are selective amylin receptor (hAMY3R) agonists (hAMY3R-EC50 ≤ 250 pM and hAM1R-EC50 ≥ 25 nM) and largely based on the human adrenomedullin fragment hAM15-52 sequence. The hAM15-52 analogues according to the invention maintain the good physical stability of hAM15-52. The invention further relates to pharmaceutical compositions comprising said polypeptides and their use in the treatment of a medical condition such as obesity, NASH and / or diabetes.

Description

hAM15-52 analogues with enhanced potency against the amylin receptor (hAMY3R) Field of invention The present invention relates to hAM15-52 analogues with enhanced potency against the amylin receptor (hAMY3R) (hAMY3R-CE50 250 pM) and which are largely based on the human adrenomedullin fragment sequence hAM15-52. The invention further relates to hAM15-52 analogues that are selective agonists of the amylin receptor (hAMY3R) (hAMY3R-CE50 250 pM and hAM1R-CE50 25 nM). In particular, the present invention is based on the observation that the human adrenomedullin fragment hAM15-52 can be converted into highly selective amylin receptor agonists (hAMY3R-CE50 250 pM and hAM1R-CE50s 25 nM) by replacing the amino acid at position X11 in hAM15-52 along with one or more of the amino acids at positions X4, X37, and / or X38 in hAM15-52. Therefore, replacing at least two amino acids in hAM15-52 results in hAM15-52 analogs with potencies against AMY3R and AM1R comparable to hAMY1-37 (amylin).The invention further relates to pharmaceutical compositions comprising said hAM15-52 analogues and their medical use in the treatment of a medical condition, such as obesity and / or diabetes. Background of the invention Obesity is a medical condition in which excess body fat accumulates to the point of negatively impacting health. It affects large numbers of people worldwide and is increasing rapidly in certain parts of the world. The World Health Organization (WHO) estimated that, in 2016, approximately 650 million people were obese globally. Obesity is defined as a body mass index (BMI) greater than 30. Obesity is considered a major risk factor for developing a variety of medical conditions, such as cardiovascular disease (e.g., hypertension, atherosclerosis, heart attacks, or strokes), NASH, musculoskeletal disorders, certain types of cancer, depression, and type 2 diabetes, and is therefore detrimental to human health. Cardiovascular disease and diabetes are two major diseases associated with obesity.A great deal of research has been carried out in the field of obesity in the search for new treatments for obesity or obesity-related diseases and disorders. Diabetes is a group of metabolic disorders characterized by high blood sugar levels. As of 2019, the International Diabetes Federation estimated that 463 million people worldwide have diabetes, with approximately half of those diagnosed. Diabetes is divided into two types: type 1 and type 2. Type 1 diabetes results from the pancreas's inability to produce enough insulin due to the loss of beta cells caused by an autoimmune response. Type 2 diabetes, on the other hand, begins with insulin resistance, in which cells do not respond properly to insulin and, as the disease progresses, can also lead to a lack of insulin. Human amylin (hAMY1-37 or amylin) is a 37-residue peptide hormone secreted along with insulin from pancreatic p cells with the amino acid sequence Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr with a disulfide bridge between residues 2 and 7. Amylin suppresses glucagon release and inhibits gastric emptying and thus plays an important role in maintaining glucose homeostasis by lowering blood sugar concentration. Therefore, amylin is a potential candidate for the treatment of diabetes. Furthermore, amylin has been shown to reduce food intake and plays an important role in satiety, making it a potential candidate for treating obesity as well.However, amylin has some drawbacks such as a high tendency to fibrillate, a short in vivo half-life, and chemical instability at pH 7. Therefore, native amylin is suboptimal for use as a pharmaceutically active ingredient. In the prior art, a large number of amylin derivatives are known, such as those disclosed in WO2016 / 146739. These amylin analogs attempt to overcome some of the known drawbacks of human amylin. A successful example is the amylin analog pramlintide, which has been approved by the FDA for use in type 1 and type 2 diabetes. However, pramlintide is formulated at pH 4 because it fibrillates at pH 7. Therefore, there is still a need for new amylin analogs with greater chemical stability, greater metabolic stability, and / or a lower tendency to fibrillate. In particular, amylin analogs that are stable over a wider pH range are desirable. Furthermore, there is a need for new amylin analogs with greater efficacy, for example, through higher potency, greater efficacy, and / or longer half-lives to allow for less frequent dosing and improved patient compliance.The present invention aims to solve one or more of the known problems of the prior art by applying a new chemical strategy. Summary of the invention In a first aspect, this disclosure relates to hAM15-52 analogues with enhanced potency against the amylin receptor (hAMY3R) (hAMY3R-CE50 at 250 pM). Therefore, in a first aspect, the disclosure relates to hAM15-52 analogues or a pharmaceutically acceptable salt thereof comprising 38 amino acids (X1-X38), wherein the amino acid at position X11 is selected from R, W, or Cit, and wherein the hAM15-52 analogue has at least 50% identity with hAM15-52 (SEQ ID NO: 1), such as at least 60% identity with hAM15-52 (SEQ ID NO: 1). The inventors surprisingly found that the position of amino acid X11 was very important for increasing the potency against the amylin receptor of hAM15-52.Therefore, a single substitution in X11 from K to R, W or Cit was sufficient to significantly improve the potency against the amylin receptor (hAMY3R-CE50 250 pM) of hAM 15-52 while preserving the potency against adrenomedullin (hAM1 R). In a second aspect, the present invention provides selective analogues of hAM15-52 (hAMY3R-CE50 250 pM and an hAM1R-CE50 > 25 nM), which act as agonists on the amylin receptor hAMY3R but, unlike the prior art (e.g., WO2016 / 146739), are derived from the backbone of the adrenomedullin fragment hAM15-52. The inventors surprisingly found that each of the X4, X37, and X38 positions was very important for the potency of hAM15-52 on hAM1R and that the potency of hAM15-52 on hAM1R could be abolished or reduced (hAM1R-CE50 > 25 nM) by certain amino acid substitutions at any of the X4, X37, and / or X38 positions.Thus, in a second aspect, the invention relates to hAM15-52 analogues comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is selected from R, W, or Cit and wherein the hAM15-52 analogue has at least 50% identity with hAM15-52 (SEQ ID NO: 1), such as at least 60% identity with hAM15-52 (SEQ ID NO: 1), and further wherein X4 is selected as F, Y, W, T, M, I, A, or C; X37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C, or K; X38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K, on ​​the condition that at least one of the positions X4, X37 or X38 does not contain the amino acid present in hAM15-52 (SEQ ID NO: 1) in that position.The inventors surprisingly found that the human adrenomedullin fragment hAM15-52 can be converted into highly selective amylin receptor agonists (hAMY3R-CE50 value ≥ 250 pM and hAM1R-CE50 > 25 nM) by replacing the amino acid at position X11 in hAM15-52 along with one or more of the amino acids at positions X4, X37, and / or X38 in hAM15-52. Therefore, replacing at least two amino acids in hAM15-52 resulted in hAM15-52 analogs with potencies on hAMY3R and hAM1R comparable to amylin instead of hAM15-52. One benefit of this approach is that, unlike human amylin, hAM15-52 is not prone to fibrillation, and by using this new chemical strategy, the inventors further predicted that the good fibrillation properties of hAM15-52 could be maintained in the new hAM15-52 analogues.Therefore, the hAM15-52 analogues according to the invention comprise a significant portion of the backbone present in hAM15-52 as a major part of the sequence (i.e., at least 50% identity with hAM15-52 (SEQ ID NO: 1)). Thus, in the second aspect of the invention, the first problem solved is the provision of novel, potent hAMY3R agonists with high selectivity for hAM1R, obtained by modifying the polypharmacology of the hAM15-52 fragment into hAMY3R agonism. The second problem solved by the second aspect is the provision of novel hAMY3R agonists that are less prone to fibrillation, thereby overcoming a problem inherent in human amylin. Unlike known prior art amylin derivatives, the hAM15-52 analogues of the present invention possess a structurally distinct sequence belonging to the hAM15-52 fragment.Therefore, the hAM15-52 analogues of the invention possess different physicochemical properties compared to amylin derivatives in the prior art, such as different solubility, chemical, physical and / or metabolic stability. In a third aspect, the invention relates to hAM15-52 analogues according to the second aspect for use as a medicament. More particularly, the third aspect of the invention relates to hAM15-52 analogues according to the second aspect for use in the treatment, prevention, or improvement of a variety of diseases, disorders, or conditions, such as, but not limited to, overeating, excess body weight, obesity, binge eating disorder, Prader-Willi syndrome, dyslipidemia, metabolic diseases / disorders, type I or II diabetes, impaired glucose tolerance, insulin resistance syndrome, and / or NASH. In a fourth aspect, the invention relates to pharmaceutical compositions comprising one or more of the hAM15-52 analogues according to the second aspect and their medical use(s) for treating, preventing, or improving a variety of diseases, disorders, or conditions according to the third aspect. The pharmaceutical compositions may comprise a carrier (vehicle) and / or one or more pharmaceutically acceptable excipients. The invention will now be explained in more detail based on the alignment of amylin (hAMY1-37) and adrenomedullin fragment (hAM15-52) as shown in Table 1 below. Definitions In the present context, when the disclosure refers to amino acid positions in the hAM15-52 analogues (i.e., X1-X38) that are derived / selected from hAMY1-37 or retained / selected from the hAM15-52 fragment, the following alignment shown in Table 1 applies. Thus, position X1 in the hAM15-52 analogues according to the invention corresponds to the first amino acid in human amylin (hAMY1-37) and to amino acid number 15 (hAM15) in the hAM15-52 fragment. hAMYi-37 KCNTATCATQRLANFLVHSSN NF - GAILSSTNVGSNTY Table 1 According to the present invention, hAM15-52 analogues are generally amidated at the C-terminus (-CONH2), like the native peptides amylin and adrenomedullin. However, the hAM15-52 analogues of the present invention may also have a free carboxylic acid (-COOH) or another post-translational modification such as a methyl ester (-COOMe). In a highly preferred embodiment of the invention, the hAM15-52 analogues are amidated at the C-terminus. The hAM15-52 analogues according to the present invention may have a free amine (-NH2), be N-acylated (-NHCOR), N-methylated (-NHCH3 or -N(CH3)2), or deaminated at the N-terminus. The hAM15-52 analogues may also be lipidated, e.g. e.g., at the N-terminus as exemplified in this document, depending on the desired half-life of the polypeptides. According to the present invention, lipidation has the meaning customary in the art. Therefore, lipidation in the present context refers to the covalent attachment of a lipid, optionally via a linker, to the hAM 15-52 analogues of the invention. Lipidization is typically performed to improve the pharmacokinetic profile of a polypeptide, e.g., by enhancing metabolic stability, reducing enzymatic degradation, decreasing excretion and metabolism, all of which result in a prolonged in vivo half-life (t1 / 2) of the hAM 15-52 analogues. The hAM 15-52 analogues according to the invention may be lipidated or non-lipidated. The lipidated hAM15-52 analogues exemplified herein are lipidated with a saturated C20 diacid through various linkers as shown in Table 2. According to the present invention, the abbreviations Hyp, Cit, Aib, Aad, (NMe) G / Sar, (NMe) I have the usual meanings in the art.Thus, Hyp refers to L-hydroxyproline, Cit refers to L-citrulline, Aib refers to 2-aminoisobutyric acid, Aad refers to L-homoglutamic acid, (NMe) G refers to N-methylglycine also known as Sar or sarcosine, and (NMe) I refers to N-methyl-L-isoleucine. According to the present invention, EC50 values ​​are used as a measure of agonist potency at a given receptor. An EC50 value is a measure of the concentration of a compound required to achieve half of that compound's maximum activity in a particular assay. Therefore, an hAM15-52 analogue according to the invention having a lower hAMY3R-EC50 than the hAMY3R-EC50 of hAM15-52 in the given assay is considered to have greater potency or activity at the hAMY3R receptor than the adrenomedullin fragment hAM15-52. Likewise, an hAM15-52 analogue according to the invention having a higher hAM1R-EC50 than the hAM1R-EC50 of hAM15-52 in the given assay may be considered to have less potency or activity at the hAM1R receptor than the adrenomedullin fragment hAM15-52. According to the present invention, an analogue of hAM15-52 or a derivative thereof may be in the form of a pharmaceutically acceptable salt. Therefore, it is intended that pharmaceutically acceptable salts include any salt commonly used in peptide formulations. Such salts include both acid addition salts and basic salts, and examples can be found, e.g., in Remington's Pharmaceutical Sciences, 17th edition. Likewise, various solvates of hAM15-52 analogues or pharmaceutically acceptable salts thereof are also within the scope of the invention. According to the present invention, the hAM15-52 analogues are short chains of amino acids linked by amide bonds. In the most preferred embodiment of the invention, the hAM15-52 analogues are 38 amino acids long, excluding any amino acids that function as a spacer between an optional lipid and the hybrid polypeptides. In the present context, unless otherwise stated, amino acids are all L-amino acids (L-stereoisomers, natural amino acids). Thus, the absolute configuration of amino acids is the (S) configuration with the exception of L-cysteine ​​and L-selenocysteine, which have the (R) configuration. In the present context, it should be understood that the amino acids Cys(X2) and Cys(X7) in the hAM15-52 analogues are covalently linked by a bridge, preferably a disulfide bridge (-SS-) such as that present in hAMY1-37 and hAM15-52. Cyclization of the disulfide bridge can be carried out after purification of the hybrid polypeptides or before resin cleavage in solid-phase peptide synthesis, optionally in the presence of suitable protecting groups. The disulfide bridge can form spontaneously by shaking the hybrid polypeptide in the presence of oxygen or can be formed by treating the hybrid polypeptides with another suitable oxidant such as iodine (I2), optionally in the presence of a base. In the present context, hAM15-52 analogues or derivatives thereof, according to the first or second aspect, have a potency against hAMY3R (CE50) of 250 pM, such as 200 pM, preferably hAMY3R-CE50 150 pM, such as 125 pM, more preferably hAMY3R-CE50 100 pM, such as 75 pM, even more preferably hAMY3R-CE50 50 pM, such as 25 pM, more preferably hAMY3R-CE50 15 pM, such as 10 pM. Therefore, the most potent hAM15-52 analogues against hAMY3R may be more or less equipotent with native human amylin hAMY1-37. For example, SEQ ID NO: 3-44 have an hAMY3R-CE50 between 6.0-10 pM and are therefore more or equipotent compared to hAMY1-37 (hAMY3R-CE50 = 10 pM) when measured under the same test conditions. In the present context, hAM15-52 analogues or derivatives thereof according to the second aspect have a suppressed or reduced EC50 when the EC50 value in hAM1R > 25 nM, such as the EC50 value in hAM1R > 50 nM, such as an hAM1R-EC50 > 100 nM, preferably an hAM1R-EC50 > 150 nM, such as > 200 nM, more preferably hAM1R-EC50 > 250 nM, such as > 300 nM, even more preferably an hAM1R-EC50 > 350 nM, such as > 400 nM, even more preferably an hAM1R-EC50 > 450 nM, such as > 500 nM, even more preferably an hAM1R-EC50 > 600 nM, such as > 700 nM, even more preferably an hAM1 R-CE50 > 800 nM, such as > 900 nM, even more preferably an hAM1R-CE50 > 1,000 nM, most preferably an hAM1R-CE50 > 5,000 nM.Therefore, in the present context, selectively in terms of potency towards the amylin receptor hAMY3R over the adrenomedullin receptor hAM1R (i.e., a selective amylin receptor agonist) should be understood as an analog of hAM15-52 or a derivative thereof according to the second aspect having an hAMY3R-CE50 value at 250 pM and an hAM1R-CE50 > 25 nM. Therefore, a selective hAM15-52 analogue or derivative thereof has a selectivity ratio (hAM1R CE5ü / hAMY3R CE50) of at least 100. Preferably, hAM15-52 analogues or derivatives thereof have an hAMY3R-CE50 value at 250 pM and an hAM1R-CE50 > 50 nM and therefore a selectivity ratio (hAM1R CE50 / hAMY3R CE50) > 200. More preferably, hAM15-52 analogues or derivatives thereof have an hAMY3R-CE50 at 200 pM, an hAM1R-CE50 > 100 nM and therefore a selectivity ratio (hAM1R CE50 / hAMY3R CE50) > 500.More preferably, an analogue of hAM15-52 or a derivative thereof has an hAMY3R-CE50 at 125 pM, an hAM1 R-CE50 > 200 nM and therefore a selectivity ratio (hAM1 R CE50 / hAMY3R CE50) > 1,600. Even more preferably, the analogue of hAM15-52 or a derivative thereof has an hAMY3R-CE50 at 100 pM, an hAM1 R-CE50 > 500 nM and therefore a selectivity ratio (hAM1 R CE50 / hAMY3R CE50) > 5,000. Ideally, the hAM15-52 analogue or a derivative thereof has an hAMY3R-CE50 at 50 pM, an hAM1 R-CE50 > 1,000 nM, and therefore a selectivity ratio (hAM1 R CE50 / hAMY3R CE50) > 20,000. For example, any of the SEQ ID NO: 3-42 has a selectivity ratio of at least 6,000, and most of them much higher. A person skilled in the art knows that EC50 values ​​depend on the type of assay and the assay conditions. Thus, in the present context, when the disclosure refers to an EC50 value, it should be understood as an EC50 value obtained when measured according to the procedure described in the examples under general protocols for cAMP assays to measure receptor activation in vitro. However, variation can also occur within the same assay under seemingly identical assay conditions due to variations in, for example, receptor expression in cells (i.e., receptor density). Therefore, in order to compare EC50 values, hAMY1-37 (SEQ ID NO: 2) and hAM15-52 (SEQ ID NO: 1) have been assayed as internal standards for comparison between different assay operations or even different assays. hAMY3R-CE50 and hAM1R-CE50 of hAMY1-37 (SEQ ID NO: 2) were determined at 10 pM and 5.hAMY3R-CE50 and hAM1R-CE50 of hAM 15-52 (SEQ ID NO: 1) were also determined at 1, 3 nM and 1, 1 nM, respectively, using the same assay conditions and cell line as the hAM15-52 analogues (SEQ ID NO: 3-392). Therefore, it follows that the hAM 15-52 analogues or derivatives thereof according to the first or second aspect have a relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAMY1-37-hAMY3R-CE50) ≈ (250 pM) / (10 pM) ≈ 25. Preferably, the relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAMY1-37-hAMY3R-CE50) ≈ 20. More preferably, the relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAM1-37-hAMY3R-CE50) ≈ 12.5. Still more preferably, the relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAMY1-37-hAMY3R-CE50) to 10. Even more preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAMY1-37-hAMY3R-CE50) to 5.Even more preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAMY1-37-hAMY3R-CE50) ≥ 2. Most preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAMY1-37-AMY3R-CE50) ≥ 1 such that the analogues of hAM15-52 or derivatives thereof are equipotent or more potent than hAMY1-37. Likewise, selective hAM15-52 analogues or derivatives thereof according to the second aspect have a relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAM15-52 - AMY3R-CE50) ≈ (250 pM) / (1,300 pM) ≈ 0.19 and a relative hAM1R-CE50 ratio (hAM1R-CE50) / (hAM15-52 - hAM1R-CE50) ≈ (25 nM) / (1.1 nM) ≈ 22.7. Preferably, the relative hAMY3R-CE50 ratio (hAMY3R-CE50) / (hAM15-52 - hAMY3R-CE50) ≈ (250 pM) / (1,300 pM) ≈ 0.19 and a relative hAM1R-CE50 (hAM1R-CE50) / (hAM1.- 52-hAM1R-CE50) > (50 nM) / (1.1 nM) > 45.5.More preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAM15-52 -hAMY3R-CE50) ≥ 0.15 and a relative ratio hAM1R-CE50 (hAM1R-CE50) / (hAM15-52 -hAM1R-CE50) > 76.9. Even more preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAM15-52 -hAMY3R-CE50) ≥ 0.096 and a relative ratio hAM1R-CE50 (hAM1R-CE50) / (hAM15-52 -hAM1R-CE50) > 154. Still more preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAM15-52 -hAMY3R-CE50) to 0.077 and a relative ratio hAM1R-CE50 (hAM1R-CE50) / (hAM15-52 -hAM1 R-CE50 ) > 384. Even more preferably, the relative ratio hAMY3R-CE50 (hAMY3R-CE50) / (hAM15-52 -AMY3R-CE50) to 0.038 and a relative ratio hAM1R-CE50 (hAM1R-CE50) / (hAM15-52 -hAM1R-CE50) > 769. More preferably, the relative ratio hAM1 R-CE50 (hAM1 R-CE50) / (hAM15-52 -hAM1 R-CE50) > 2.000. According to the present invention, the term "treatment" is to be understood in its broadest sense as prevention, improvement, or treatment. Therefore, it is also intended that treatment includes prophylactic treatment. According to the present invention, the aspect or aspects / embodiment or embodiments referring to "where the analogue of hAMi5-52 has (e.g.) at least 50% identity with hAMi5-52 (SEQ ID NO: 1)" or "a derivative thereof with (e.g.) at least 50% identity with hAMi5-52" shall be understood to mean that the analogue of hAM15-52 or a derivative thereof has at least 50% sequence identity with hAM15-52 (SEQ ID NO: 1) when aligned. As an example, the SEQ ID NO: 169 illustrated below differs by two amino acids (X11 and X38) from hAM15-52 (SEQ ID NO: 1) and, therefore, has (38-2) / 38 = 94.7% sequence identity with hAM15-52 (SEQ ID NO: 1). SEQ ID NO:1 G C R F G T C T V Q K L A H Q I Y Q F T D K D K D N V A P R S K I S P Q G Y Derivado X: G C R F G T C T V Q R L A H Q I Y Q F T D K D K D N V A P R S K I S P Q G Hyp Descripción detallada de la invención La familia de péptidos de calcitonina The calcitonin peptide family consists of the hormonal peptides calcitonin (CT), calcitonin gene-related peptide (CGRP), islet amyloid polypeptide (IAPP, amylin, or hAMY1-37), and adrenomedullin (hAM), as well as their precursors. hAMY1-37 is a 37-residue peptide hormone that is co-excreted with insulin from pancreatic p cells with the amino acid sequence Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr. Amylin suppresses glucagon release and inhibits gastric emptying, thus playing an important role in maintaining glucose homeostasis by lowering blood sugar levels. Furthermore, amylin has been shown to reduce food intake and play a significant role in satiety, making it a potential candidate for treating, for example, [conditions].obesity and / or diabetes. hAM is a 52-residue peptide hormone expressed in all tissues with the amino acid sequence Tyr-Arg-Gln-Ser-Met-Asn-Asn-Phe-Gln-Gly-Leu-Arg-Ser-Phe-Gly-Cys-Arg-Phe-Gly-Thr-Cys-Thr-Val-Gln-Lys-Leu-Ala-His-Gln-Ile-Tyr-Gln-Phe-Thr-Asp-Lys-Asp-Lys-Asp-Asn-Val-Ala-Pro-Arg-Ser-Lys-Ile-Ser-Pro-Gln-Gly-Tyr. It is a potent vasodilator and has shown a positive influence on cardiovascular diseases, such as myocardial infarction, limb ischemia, and hypertension. The biological activity of the calcitonin protein family is generally mediated by binding to the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CRLR), both belonging to the G protein-coupled receptor (GPCR) family 2. These receptors can be co-expressed in combination with different receptor-modifying proteins (RAMP1-3), generating functional receptors for individual peptides in the calcitonin protein family. Co-expression of CTR with RAMP1 leads to the formation of a receptor for amylin and CGRP (AMY1R), co-expression of CTR with RAMP2 leads to amylin receptor 2 (AMY2R), and co-expression of CTR with RAMP3 leads to amylin receptor 3 (AMY3R).Co-expression of CRLR with RAMP1 leads to the formation of a receptor for CGRP (CGRP1R), co-expression of CRLR with RAMP2 leads to the formation of a receptor for adrenomedullin (AM1R), and co-expression of CRLR with RAMP3 leads to the formation of a receptor for both adrenomedullin and CGRP (AM2R). Several of the native peptides of the calcitonin protein family show considerable overlap in pharmacology between receptors. For example, adrenomedullin is approximately 100 times less potent at AMY3R compared to hAMY1-37. The adrenomedullin fragment (hAM15-52) is nearly equipotent at AMY3R and AM1R, with an EC50 of 1.3 nM at AMY3R and 1.1 nM at AM1R (these EC50 values ​​are based on the examples in this document). hAMY1-37, on the other hand, has an EC50 of 10 pM at AMY3R while being inactive at AM1R. Determination of important amino acid positions in hAMis-52 The inventors initially hypothesized that, since hAM15-52 and hAMY1-37 belong to the same hormone family, the Calcitonin / CGRP / IAPP family, the potency of hAM15-52 at AMY3R could be enhanced or even converted into selective AMY3R agonism over hAM1R agonism by substituting certain amino acids in hAM15-52 with amino acids derived from hAMY1-37, thus overcoming some of the drawbacks inherent in hAMY1-37. All 37 amino acids of hAMY1-37 were systematically substituted in hAM15-52. In addition, X38 was selected as Hyp (Hydroxyproline), which is not present in either hAMY1-37 or hAM15-52. The inventors built random forest models (Breiman, L. (2001), Random Forests, Machine Learning 45 (1), 5-32.) that describe the relationship between peptide sequence and hAMY3R and power on hAM1R, respectively, and systematically synthesized and screened peptide sequences.For each hAM15-52 analog, the amino acid at each sequence position was used as a feature, and the receptor's CE50 values ​​were used as the response to build the models. The "randomForest" package, implemented in the R statistical programming language, was used to calculate the importance of each position, and the most important positions were identified as critical for hAMY3R and / or hAM1R activity (A. Liaw and M. Wiener (2002). Classification and Regression by randomForest. R News 2 (3), 18-22). Based on this systematic analysis, the inventors identified X4, X37, and X38 as important for hAM1R activity, while they were less important for hAMY3R activity. The inventors also identified X11 as critical for hAMY3R activity, while it was less important for hAM1R activity.Finally, the inventors identified that X17 is of some importance for hAMY3R activity, while it is less important for hAM1R activity. Therefore, the inventors identified X11 as a key position for enhancing the potency against hAMY3R in hAM15-52 and X4, X37, and X38 as key positions for eliminating the potency against hAM1R in hAM15-52. Since X17 was only of some importance for hAMY3R activity, this position was not considered a key position but rather a preferred position for further enhancing the potency against AMY3R of the hAM15-52 analogs. Systematic investigation showed that the potency against hAMY3R of hAM15-52 could be improved by replacing the amino acid K present in hAM15-52 at position X11 with the amino acid R present in hAMY1-37. Furthermore, systematic investigation showed that the potency against hAM1R of hAM15-52 could be decreased by replacing the amino acids present at positions X4, X37, and X38 in hAM15-52 with the corresponding amino acids found in hAMY1-37. Further investigation of amino acids at positions X4, X11, X17, X37 and X38. The inventors systematically substituted representative amino acids covering all known amino acids at the five identified positions, one position at a time (Table 6). As shown in Example 1, all (SEQ ID: 1–360) had lost their activity in hAM1R, with varying degrees of potency in AMY3R. In order to rate the individual amino acids at the five positions, the average EC50 value for peptides containing a given amino acid at a given position was compared to the average EC50 value of hAM15–52 analogs containing the reference amino acid at that position. Given a potency change cutoff of 4-fold, each amino acid at each position was rated as giving increased (I), decreased (D), or no change (U) potency, relative to the reference amino acid, in hAMY3R. The results are summarized in Table 6.Based on these data, it was shown that any of the amino acids R, W, or Cit were able to maintain potency against AMY3R when present at position X11 compared to the reference, while other representative amino acids decreased potency. It was further shown that any of the amino acids Y, W, T, M, I, F, A, or C at X4, any of the amino acids Y, W, T, Q, P, M, I, H, F, E, A, R, C, or K at X37, and any of the amino acids Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K at X38 were able to maintain or improve potency against AMY3R, while remaining inactive against hAM1R. Aspect 1: hAMw-52 analogues with enhanced amylin potency Thus, in a first aspect, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising 38 amino acids (X1-X38) with an hAMY3R-CE50 250 pM, wherein the amino acid at position X11 is selected from R, W or Cit and wherein the analogue of hAM15-52 has at least 50% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52 (SEQ ID NO: 1).From Example 1 (Table 2), it can be seen that almost all synthesized hAM15-52 analogs have at least 50% identity with hAM15-52, that the vast majority of synthesized hAM15-52 analogs have at least 60% identity with hAM15-52, and that a large proportion of synthesized hAM15-52 analogs have at least 80% identity with hAM15-52 (SEQ ID NO: 1). All these hAM15-52 analogs maintain the good fibrillation properties of hAM15-52 (SEQ ID NO: 1) compared to hAMY1-37 (SEQ ID NO: 2) (see Example 2, Table 3). E.g., SEQ ID NO: 32 shows that the good physical stability (i.e., low fibrillation) of hAM15-52 can be maintained as long as hAM15-52 analogues have at least 50% identity with hAM15-52. Therefore, in one respect, the disclosure relates to a way of greatly improving the potency against hAMY3R of the hAM15-52 fragment by a single substitution to R, W, or Cit at the X11 position, while maintaining good physical stability (i.e., good fibrillation properties of hAM15-52). These hAM15-52 analogs will thus be very potent agonists at both hAMY3R and hAM1R (see SEQ ID NO: 361-392). In the most preferred embodiment of the disclosure, X11 is selected as R. In another embodiment, X11 is selected as W. In yet another embodiment, X11 is selected as Cit. The inventors found that this single amino acid substitution in X11 provided increased potency against hAMY3R to the hAM15-52 analogues while preserving potency against hAM1R. The inventors further found that the potency against hAMY3R could be maintained when X17 was Y, T, Q, M, I, F, A, R, or K, or even further improved by selecting X17 as W or H. Therefore, in one embodiment, X17 is selected as Y, W, T, Q, M, I, H, F, A, R, or K. In a preferred embodiment, X17 is selected as Y, W, or H, more preferably W or H. In one embodiment, the disclosure relates to an analogue of hAM15-52 comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is selected from R, W, or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K, preferably X17 is selected as W or H and wherein the analogue of hAM15-52 has at least 50% identity with hAM15-52, such as at least 60% identity with hAM 15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM 15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52 (SEQ ID NO: 1). In a further embodiment, the disclosure relates to an analogue of hAM15-52 comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is R; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K, preferably X17 is selected as W or H and wherein the analogue of hAM15-52 has at least 50% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, (SEq ID NO: 1). In a further embodiment, the invention relates to an analogue of hAM15-52 comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is W; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K, preferably X17 is selected as W or H and wherein the analogue of hAM15-52 has at least 50% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAMi5-52, more preferably at least 80% identity with hAMi5-52, such as at least 85% identity with hAM15-52, (SEQ ID NO: 1). In a further embodiment, the disclosure relates to an analogue of hAM15-52 comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K, preferably X17 is selected as W or H and wherein the analogue of hAM15-52 has at least 50% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, (SEQ ID NO: 1). In a preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): and where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K. In another preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K. In a more preferred embodiment, the disclosure relates to an analogue of hAMi5-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A, or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R;| X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C, or K; X38 is selected from Hyp, Y, W, M or F. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F. In an even more preferred further embodiment, the disclosure relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; or a derivative thereof with at least 50% identity with hAM15-52, preferably at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, even more preferably at least 85% identity with hAM15-52, such as at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R; X17 is selected as Y, W or H; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F. In a further more preferred embodiment, the disclosure relates to an analogue of hAM15-52 comprising the amino acid sequence of formula (I): where, X11 is selected from R, W or Cit or a derivative thereof with at least 50% identity with hAM15-52, at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least a 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, more preferably at least 90% identity with hAM15-52 with hAM15-52, such as at least 95% identity with hAM15-52, wherein X11 is selected from R, W or Cit. In a most preferred embodiment, the disclosure relates to an analogue of hAM15-52 of SEQ ID NO: 3-392 or a derivative thereof having at least 90% identity with any one of SEQ ID NO: 3-392, preferably at least 95% identity with any one of SEQ ID NO: 3-392, more preferably at least 96% identity with any one of SEQ ID NO: 3-392, most preferably at least 97% identity with any one of SEQ ID NO: 3-392, provided that a derivative thereof has R, W or Cit at position X11, preferably R at position X11. In a most preferred embodiment, the disclosure relates to an analogue of hAM15-52 of SEQ ID NO: 3-392 or a derivative thereof having at least 90% identity with any one of SEQ ID NO: 3-392, preferably at least 95% identity with any one of SEQ ID NO: 3-392, more preferably at least 96% identity with any one of SEQ ID NO: 3-392, most preferably at least 97% identity with any one of SEQ ID NO: 3-278, provided that a derivative thereof has the same amino acid at position X11 as the respective one of SEQ ID NO: 3-392 from which it is derived. Aspect 2: Selective hAMi5-52 analogues with enhanced amylin potency Number of positions needed to suppress or reduce power on AM1R in I1AM 15-52. The inventors found that the potency on hAM1R could be suppressed or reduced at hAM15-52 by changing at least one amino acid at any of the X4, X37, or X38 positions, as all of them were critical for potency on hAM1R. Decreased potency on hAM1R with amino acids at position X4, X37 or X38. X4: The inventors found that amino acids Y, W, T, M, I, A, or C at position X4 were able to decrease the potency of hAM1R. Therefore, in one embodiment, X4 is selected from Y, W, T, M, I, A, or C. Furthermore, amino acids W, M, I, or C at position X4 were most effective in enhancing the potency of hAMY3R (see Example 5, Table 6). Therefore, in a highly preferred embodiment of the invention, X4 is selected as W, M, I, or C. Since the inventors found that a single position chosen from X4, X37, or X38 was sufficient to suppress or reduce the potency of AM1R, it follows that, in some embodiments, X4 is F (i.e., the native amino acid present in hAM15-52 (SEQ ID NO: 1) at that position), and the potency of AM1R is suppressed or reduced using position X37 and / or X38. Therefore, in any of the above embodiments for X4, F can be included and the power on AM1R can be suppressed or reduced using position X7 and / or X38. X37: The inventors also found that amino acids Y, S, W, T, Q, P, M, I, H, F, E, A, R, and C at position X37 were able to decrease the potency of hAM1R. Thus, in one embodiment, X37 is selected from Y, S, W, T, Q, P, M, I, H, F, E, A, R, and C. Furthermore, amino acids Y, W, P, H, or F at position X37 were most effective in improving the potency of hAMY3R (see Example 5, Table 6). Therefore, in a highly preferred embodiment of the invention, X37 is selected as Y, W, P, H, or F. Since the inventors found that a single position chosen from X4, X37, or X38 was sufficient to suppress or reduce the potency of AM1R, it follows that in some embodiments X37 is G (i.e., the native amino present in hAM15-52 (SEQ ID NO: 1) at that position), and the potency of AM1R is suppressed or reduced using position X4 and / or X38.Therefore, in any of the above realizations for X37, G can be included and the power on AM1R can be suppressed or reduced using position X4 and / or X38. X38: The inventors also found that the amino acids Hyp, W, T, Q, P, M, I, H, F, E, A, R, or K at position X38 were able to decrease the potency of hAM1R. Therefore, in one embodiment, X38 is selected from Hyp, W, T, Q, P, M, I, H, F, E, A, R, or K. Furthermore, the amino acids Hyp, W, M, or F were the most effective in improving the potency of hAMY3R (see Example 5, Table 6). Therefore, in a highly preferred embodiment of the invention, X38 is selected as Hyp, W, M, or F. In the most preferred embodiment of the invention, X38 is selected as Hyp. Since the inventors found that a single position chosen from X4, X37 or X36 was sufficient to suppress or reduce the potency on AM1R, it follows that in some embodiments X38 is Y (i.e., the native amino present in hAM15-52 (SEQ ID NO: 1) at that position), and the potency of AM1R is suppressed or reduced using position X4 and / or X37.Therefore, in any of the above embodiments for X38, Y can be included and the power on AM1R can be suppressed or reduced using position X4 and / or X37. A simple illustration of aspect 2 of the invention can be seen by comparing the alignment of hAM15-52 (SEQ ID NO: 1) and SEQ ID NO: 169 shown below. SEQ ID NO:1 GCRFGTCTVQKLAHQIYQFTD KDKDNVAPRSKISPQGY SEQ ID NO:169 GCRFGTCTVQRLAHQIYQFTD KDKDNVAPRSKISPQG Hyp SEQ ID NO:1 hAMY3R CE501, 274 nM and hAM1 R CE501, 113 nM SEQ ID NO:169 hAMY3R CE500, 063 nM and hAM1 R CE502.981, 0 nM As can be seen, the R at position X11 has improved the potency of AMY3R approximately 20-fold, and the Hyp at position X38 has decreased the potency of AM1R approximately 2,500-fold. Therefore, only two substitutions have converted hAM15-52 into an amylin agonist with the same pharmacological profile as hAMY1-37. At the same time, SEQ ID NO: 169 has maintained the physical stability (ThT signal: 2,700%) of hAM15-52 (ThT signal: 2,600%) compared to hAMY1-37 (ThT signal: 100.0%) (see Example 2, Table 3). Thus, in a second aspect, the invention relates to a means of more or less completely suppressing the potency against hAM1R of the hAM15-52 fragment by means of one or more substitutions at positions X4, X37, and / or X38, while simultaneously improving or maintaining sufficient potency against AMY3R. These hAM15-52 analogs will therefore be highly potent and selective hAMY3R analogs.At the same time, these hAM15-52 analogs maintain the physical stability of hAM15-52 due to their sequence identity with hAM15-52. As shown in Example 2, Table 3, the good physical stability of hAM15-52 can be maintained or even improved in the peptides (due to at least 50% identity with hAM15-52), while providing novel hAMY3R agonists that are as potent and selective as natural human amylin. In other words, the second aspect of the present invention has created a functional human amylin analog concealed within an adrenomedullin backbone. Increased potency over hAMY3R with amino acids at position X 17. The inventors further found that the power over hAMY3R could be maintained when X17 was Y, T, Q, M, I, F, A, R, or K, or even improved further when X17 was W or H. Thus, in one embodiment, X17 is selected as Y, W, T, Q, M, I, H, F, A, R, or K. In a preferred embodiment, X17 is selected as W or H. Thus, in a second aspect, the invention relates to hAM15-52 analogues comprising 38 amino acids (X1-X38) or a pharmaceutically acceptable salt thereof, wherein the amino acid at position X11 is selected from R, W, or Cit, and wherein the hAM15-52 analogue has at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, most preferably at least 90% identity with hAM15-52, such as at least 95% identity with hAM15-52 (SEQ ID NO: 1) and further wherein X4 is selected as F, Y, W, T, M, I, A or C; X37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K;X38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K, provided that at least one of positions X4, X37, or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; more preferably, at least two of positions X4, X37, or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. Secondly, the hAM15-52 analogues have an hAMY3R-CE50 of 250 pM and an hAM1R-CE50 of 25 nM. In one embodiment, X4 is selected as F, W, M, I or C; X37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K, with the condition that at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position, more preferably, at least two of the positions X4, X37 or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In one embodiment, X4 is selected as F, Y, W, T, M, I, A or C; X37 is selected as G, Y, W, P, H or F; X38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K, on ​​the condition that at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position, more preferably, at least two of the positions X4, X37 or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In one embodiment, X4 is selected as F, Y, W, T, M, I, A or C; X37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected as Hyp, Y, W, M or F, on the condition that at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position, more preferably at least two of the positions X4, X37 or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In one embodiment, X4 is selected as F, W, M, I or C; X37 is selected as G, Y, W, P, H or F; X38 is selected as Hyp, Y, W, M or F, with the condition that at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position, more preferably at least two of the positions X4, X37 or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R, K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) in that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity, even more preferably at least 85% identity, such as at least 90% identity, most preferably at least 95% identity, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R, K; X4 is selected from F, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and further wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a further more preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity, such as at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In another more preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W, or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R, or K; X4 is selected from F, Y, W, T, M, I, A, or C; X37 is selected from G, Y, W, P, H, or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity, such as at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a further more preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAMi5-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52) preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity, such as at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a further more preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM^ - 52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM^ -52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM^ -52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM^ -52, such as at least 85% identity with hAM15-52, more preferably at least 90% identity with hAM^ -52, most preferably at least 95% identity with hAM^ -52, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a preferred embodiment of the invention, it refers to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52) preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, more preferably at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, M or F; and further wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity, such as at least 85% identity with hAM15-52, more preferably at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In a more preferred embodiment, the invention relates to an analogue of hAM15-52 or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of formula (I): where X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM 15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 85% identity with hAM15-52, more preferably at least 90% identity with hAM15-52, most preferably at least 95% identity with hAM15-52, wherein X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, W, M, I or C; X37 is selected from G, Y, W, P, H or F; X38 is selected from Hyp, Y, W, M or F; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (s Eq ID NO: 1) at that position. In any of the embodiments mentioned above, X11 is most preferably R, and / or X17 is most preferably Y, W, or H. Furthermore, in any of the embodiments mentioned above, most preferably at least two of the positions X4, X37, or X38 are not the amino acids present in hAM15-52 (SEQ ID NO: 1) at that position. In a more highly preferred embodiment, the invention relates to an analogue of hAM15-52 having the sequence SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360 or a derivative thereof having at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, preferably at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52, more preferably at least 80% identity with hAM15-52, such as at least 90% identity with hAM 15-52 (SEQ ID NO: 1), wherein, in the derivative, X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, Mv, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K;and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position.; In a further highly preferred embodiment, the invention relates to an analogue of hAM15-52 having the sequence SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360 or a derivative thereof having at least 90% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, preferably at least 95% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, most preferably at least 97% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308 360, on the condition that in the derivative, X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C;X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position.; In any of the embodiments mentioned above, X4 is preferably selected as F, W, M, I, or C; X11 is preferably selected as R; X37 is preferably selected as G, Y, W, P, H, or F; X38 is preferably selected as Hyp, Y, W, M, or F; X17 is preferably selected as W or H. Furthermore, in any of the embodiments mentioned above, most preferably at least two of the positions X4, X37, or X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position. In the most preferred embodiment, the invention relates to an analogue of hAM15-52 having the sequence of SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, or a derivative thereof having at least 90% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, preferably at least 95% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, most preferably at least one 97% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, provided that a derivative thereof has the same amino acids at positions X4, X11, X37, and X38, preferably the same amino acids at positions X4, X11, X17, X37, and X38, as the respective hAM15-52 analogue of SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 18.- 206, 208-243, 246-305, or 308-360 from which it is derived. Medical use In a third aspect, the invention relates to hAM15-52 analogues according to the second aspect for use as a medicament. More particularly, the third aspect of the invention relates to hAM15-52 analogues according to the second aspect for use in the treatment, prevention, or improvement of a variety of diseases, disorders, or conditions, such as, but not limited to, overeating, excess body weight, obesity, binge eating disorder, Prader-Willi syndrome, dyslipidemia, metabolic diseases / disorders, type I or type II diabetes, impaired glucose tolerance, insulin resistance syndrome, and / or NASH. A preferred embodiment relates to one or more hAM15-52 analogues for use in the treatment of obesity, diabetes, NASH, or combinations thereof. Pharmaceutical compositions In a fourth aspect, the invention relates to pharmaceutical compositions comprising one or more of the hAM15-52 analogues according to the second aspect and their medical use(s) for treating, preventing, or improving a variety of diseases, disorders, or conditions according to the third aspect. The pharmaceutical compositions may comprise a pharmaceutically acceptable carrier (vehicle) and / or one or more excipients according to conventional techniques in the art, such as those described in 'Remington: Essentials of Pharmaceutics', edited by Linda A. Felton, Pharmaceutical Press 2012. Suitable formulations include, but are not limited to, tablets, pills, capsules, emulsions, suspensions, sustained-release formulations, or solutions. It should be appreciated that different routes of administration may be used depending on the choice of formulation and the chemical and / or metabolic stability of the polypeptides. Such routes of administration may include, but are not limited to, oral administration, parenteral administration (intravenous (IV), subcutaneous (SC), intradermal (ID), and intramuscular (IM)), or inhalation. In a preferred embodiment of the invention, the route of administration is parenteral. In a further preferred embodiment, the route of administration is subcutaneous. Examples General protocols for the synthesis of hybrid polypeptides The peptides were synthesized using a fully automated SyroII parallel peptide synthesizer (MultiSynTech GmbH, Germany), equipped with a heating block, on Tentagel 5 RAM with a loading of 0.23–0.25 mmol / g (Rapp Polymer GmbH, Germany). Na-Fmoc deprotection was performed in two steps by treating the resin with piperidine. 40% / DMF (0.2 M HOBt (1-hydroxybenzotriazole)) for 3 min at 45 °C, followed by 20% / DMF (0.1 M HOBt) piperidine for 7–12 min at 75 °C. Except for Asp, Cys, and His residues, which were deprotected from Na-Fmoc at room temperature; i.e., 40% / DMF (0.2 M HOBt) piperidine for 3 min followed by 20% / DMF (0.1 M HOBt) piperidine for 15 min. The coupling chemistry was DIC (N,N'-diisopropyl-carbodiimide) / Oxime (ethyl cyano(hydroxyimino) acetate) in d Mf using 0.5 M amino acid solutions in DMF and a 6-fold molar excess. Standard Fmoc-protected amino acids were used. Coupling conditions were single or double coupling for 15 min at 75 °C, except for His and Cys residues, which underwent double coupling for 15 min at 50 °C. Fmoc amino acids were dissolved at 0.5 M in DMF containing 0.5 M oxime, except for His, which was dissolved in NMP.The resin was washed 4 times with NMP after deprotection with Na-Fmoc and 3 times after couplings. The disulfide bridge was formed in the resin using Trityl (Trt) as a protecting group for cysteine ​​and treating it with 1% iodine in 75% HFIP (Hexafluoroisopropanol) in DCM for 1 min. The resin was washed 3 times with 75% HFIP in DCM followed by 4 times with DCM. After synthesis, the resin was washed with DCM and dried, and the polypeptide was cleaved from the resin by a treatment of 35 min with TFA (trifluoroacetic acid) / TES (triethylsilane) / water (95 / 2, 5 / 2, 5) at 42 °C, followed by precipitation with 4 volumes of cold diethyl ether, further washing with diethyl ether and allowed to dry. The peptides were characterized by LC-MS (Waters, Denmark) and quantified by LC-CAD (ThermoFisher Scientific, Denmark). Finally, the peptides were lyophilized to a white powder using a Telstar benchtop freeze dryer. General protocols for cAMP assays to measure receptor activation in vitro hAMY3-R: Cells stably overexpressing the hAMY3 receptor from Ogeda (now Astellas Pharma) were obtained, subcloned, and a monoclonal cell line with an appropriate assay window was expanded, aliquoted, and frozen. An aliquot was thawed and plated on DPBS containing 0.05% casein and 0.5 mM IBMX at a density of 2,000 cells / well in a 384-well format. The cells were then immediately stimulated for 30 min at room temperature with graded doses of the assay compound using human amylin (Bachem, cat. no. H-7905) as a positive control. cAMP accumulation was measured using a Cisbio assay for Gs-coupled receptors (cat. no. 62AM4PEC), where the assay reagents were added according to the manufacturer's instructions and time-resolved fluorescence energy transfer was recorded after one hour. hAM1-R: Cells stably overexpressing the hAM1 receptor from Ogeda (now Astellas Pharma) were obtained, subcloned, and a monoclonal cell line with an appropriate assay window was expanded, aliquoted, and frozen. An aliquot was thawed and plated on DPBS containing 0.05% casein and 0.5 mM IBMX as 8,000 cells / well in a 384-well format. The cells were then immediately stimulated for 30 min at room temperature with graded doses of the assay compound using human adrenomedullin 1-52 (Bachem, cat. no. H-2932) as a positive control. cAMP accumulation was measured using a Cisbio assay for Gs-coupled receptors (cat. no. 62AM4PEC), where the assay reagents were added according to the manufacturer's instructions and time-resolved fluorescence energy transfer was recorded after one hour. General protocols for determining the physical stability of peptide analogues The peptides were dissolved in buffers (50 mM sodium acetate at pH 4 or 50 mM sodium phosphate at pH 7) and incubated for one hour. The samples were then divided into two 80 µL replicates in a 384-well black plate (p-clear, Greiner Bio-One) and mixed with thioflavin T (ThT) to a final concentration of 4 pM. The plate was sealed and placed in a plate reader (CLARIOstar, BMG) where the temperature was set at 40 °C for the duration of the experiment. The samples were further strained by shaking the plate at 700 rpm (linear) for five minutes before each measurement. Fluorescence was measured every 10 minutes for four days by exciting ThT at 450 nm and measuring the emission at 480 nm. For each peptide, the ThT signal over time was smoothed using the Local Polynomial Regression Fit (LOESS) implemented in the R statistical programming environment.For the smoothed data, the peak ThT signal was normalized as a percentage between the peak ThT signal for hAMY and the buffer background. Therefore, high values ​​indicate fibrillation properties similar to hAMY, while low values ​​indicate no fibrillation. General protocols for the study of acute food intake The effect on cumulative food intake was measured in male Sprague Dawley rats (6 weeks old, Taconic, Denmark) after a single dose using a fully automated food intake monitoring system (HM-2; MBROse ApS, Faaborg, Denmark), which allowed for advanced, synchronous, real-time monitoring of individual animal feeding behavior. Animals were housed in groups of four in a room with controlled light, temperature, and humidity (12 / 12 LD cycle, lights on at 02:00 AM; 22 ± 2 °C; 50% relative humidity). Mice had ad libitum access to a regular feed diet (Altromin 1324, Brogaarden NS, Lynge, Denmark) and domestic-quality tap water. Mice arrived on day 7, and a minimum of five days of habituation to the system was allowed before the start of the study. During these days, the animals were handled daily to accustom them to the experimental paradigm.On the day of dosing, animals were randomized into groups according to body weight. Animals were fasted for four hours prior to dosing. Animals received subcutaneous (SC) doses 30 or 180 minutes before lights out, and food intake data were automatically collected for a total of 48 hours post-dosing with automatic food recordings every 5 minutes. General protocols for the study of diet-induced chronic obesity (DIO) Sprague-Dawley rats (Taconic, Denmark) reached 5 weeks of age. After one week of acclimation, they were evenly grouped according to their baseline body weight and offered ad libitum access to a two-choice diet consisting of feed pellets (Altromin #1324, Brogaarden, Lynge, Denmark) and a highly palatable high-sugar / high-fat diet (1:1:1 mixture of Nutella (Ferrero, Alba, Italy), peanut butter (PCD, Rotterdam, Netherlands), and standard powdered feed (Altromin #1324, Brogaarden, Lynge, Denmark); 29.3% fat, 33.2% carbohydrate, and 18% protein) for up to 36 weeks. Rats were housed in pairs throughout the study under controlled environmental conditions (12-hour light / dark cycle, lights off at 3:00 PM; 22 ± 1 °C; 50 ± 10% relative humidity). Body weight and food and water intake were monitored daily throughout the study period.One day before the experiment, the rats were randomized according to body weight into experimental groups (n = 9-10), which received compound or vehicle SC. QD (once a day) for 28 days. Example 1 The CE50 values ​​for hAMY3R and hAM1R were measured according to the general protocol described above. The percent identity for the hAM15-52 analogs was calculated in comparison to hAM15-52. The results are summarized in Table 2 below. Table 2. Table 2 shows that hAM15-52 analogs (SEQ ID NO: 3-392) with enhanced potency against hAMY3R compared to hAM15-52 can be obtained by changing the amino acid K present in hAM15-52 at position X11 to R, W, or Cyt. Table 2 further shows that hAM15-52 analogs highly selective for hAMY3R (hAMY3R-CE50 250 pM and hAM1R-CE50 s 25 nM) (SEQ ID NO: 3-360) can be obtained by suppressing or reducing potency against hAM1R using positions X4, X37, and / or X38. All lipidations at position 1 were performed at the N-terminus, and lipidations at the other positions were performed at an N-epsilon at Lys. AMCHC refers to trans-4-(aminomethyl)cyclohexanecarboxylic acid. OEG refers to 8-amino-3,6-dioxaoctanoic acid or 8Ado. Example 2 Fibrillation was determined according to the general protocol for determining the physical stability of peptide analogues. Data for the selected hAM15-52 analogues are summarized in Table 3 below. Table 3. Table 3 shows that the hAM15-52 analogues according to the invention maintain the good fibrillation properties of hAM15-52. Most of the fibrillation data are comparable to, and some even better than, hAM15-52 (SEQ ID NO: 1) at pH 7 (ThT signal of 2.6%). All fibrillation data are significantly superior compared to the reference hAMY1-37 (SEQ ID NO: 2) (ThT signal at 100%). Example 3 The effect of selected hAMi 5-52 analogues on acute food intake in lean rats was determined. The results are summarized in Table 4 below. Table 4. Table 4 shows that hAM15-52 analogues have potent anorexigenic effects up to 48 hours after a single SC injection in lean healthy rats (n=7-8), thus providing proof of principle. One-way linear model of Dunnett's test***: P < 0.001 compared to the vehicle (three independent operations were performed). Example 4 The effect of chronic treatment with selected hAMi 5-52 analogues according to the invention was determined in diet-induced obesity (DIO) rats. The results are summarized in Table 5 below. Table 5. Table 5 shows that daily SC injections of SEQ ID NO: 46 or 78 cause a significant reduction in body weight in diet-induced obese rats (n = 10) after a 28-day treatment period, thus providing proof of concept. One-way linear model Dunnett's test***: P < 0.001 compared to vehicle (two independent operations were performed). Example 5 Further investigation of representative amino acids at positions X4, X11, X17, X37, and X38 and the corresponding change in potency. The results are summarized in Table 6 below. Table 6. Table 6 shows whether the amino acid change results in an increase (I) in potency over hAMY3R, no change in potency (U), or decreased potency (D) compared to the reference amino acid (R). N / A Not available. Table 7. LIST OF SEQUENCES _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Table 7 continued. _ _ _ _ _ _

Claims

1. An analogue of hAMi5-52 or a pharmaceutically acceptable salt thereof comprising 38 amino acids (X1-X38) with an hAMY3R-CE50 ^ 250 pM and an hAM1 R-CE50 ^ 25 nM, wherein the amino acid at position X4 is selected as F, Y, W, T, M, I, A or C; X37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; X11 is R, W, or Cit, wherein at least one of the positions X4, X37, or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position, and further wherein the hAM15-52 analogue has at least 50% identity with hAM15-52 (SeQ ID NO: 1).

2. An hAM15-52 analogue or a pharmaceutically acceptable salt thereof according to claim 1, wherein the hAM15-52 analogue has at least 60% identity with hAM15-52, such as at least 70% identity with hAM15-52.preferably at least 80% identity with hAM15-52 (SEQ ID No: 1).

3. An analogue of hAM15-52 or a pharmaceutically acceptable salt thereof according to claim 1, comprising the amino acid sequence of formula (I): wherein X11 is selected from R, W or Cit; X17 is selected from Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position; or a derivative thereof with at least 50% identity with hAM15-52, such as at least 55% identity with hAM15-52, such as at least 60% identity with hAM15-52, such as at least 65% identity with hAM15-52, or at least 70% identity with hAM15-52, such as at least 75% identity with hAM15-52,more preferably at least 80% identity with hAM15-52, such as at least 90% identity with hAM15-52, preferably at least 95% identity with hAM15-52, wherein, in the derivative, X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and furthermore where at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position.

4. An analogue of hAM15-52 or a pharmaceutically acceptable salt thereof according to claim 1 having the sequence of SEQ ID NO: 3-57, 60-75, 77-79, 8-92, 94-127, 129-147, 150-161, 163-179, 18-206, 208-243, 246-305 or 308-360 or a derivative of any of the same having at least 90% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127,129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, preferably at least 95% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, most preferably at least 97% identity with any one of the SEQ ID NO: 3-57, 60-75, 77-79, 81-92, 94-127, 129-147, 150-161, 163-179, 181-206, 208-243, 246-305, or 308-360, provided that in the derivative, X11 is selected from R, W or Cit; X17 is selected as Y, W, T, Q, M, I, H, F, A, R or K; X4 is selected from F, Y, W, T, M, I, A or C; X37 is selected from G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C or K; X38 is selected from Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R or K; and further wherein at least one of the positions X4, X37 or X38 is not the amino acid present in hAM15-52 (SEQ ID NO: 1) at said position.

5. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims,wherein at least two of the positions X4, X37, and X38 are not the amino acid present in hAM15-52 (SEQ ID NO: 1) at that position.

6. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein all positions X4, X37, and X38 are selected as follows: X4 is selected from Y, W, T, M, I, A, or C; X37 is selected from Y, S, W, T, Q, P, M, I, H, F, E, A, R, C, or K; X38 is selected from Hyp, W, T, Q, P, M, I, H, F, E, A, R, or K; 7. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein X4 is selected as F, W, M, I, or C.

8. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein X37 is selected as G, Y, W, P, H, or F.

9. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein X38 is selected as Hyp, Y, W,M or F.

10. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein X17 is selected as W or H.

11. An analogue of hAM15-52 or a derivative thereof according to any of the preceding claims, wherein X11 is R.

12. An analogue of hAM15-52 or a derivative thereof according to any of claims 1-11 for use as a medicament.

13. A pharmaceutical composition comprising an analogue of hAM15-52 or a derivative thereof according to claims 1-11, a pharmaceutically acceptable vehicle, and optionally one or more excipients.