Soluble NPY2 receptor agonists

Abstract

The present invention relates to PYY analogs having an alanine at position 4, a lysine at position 7, a QRY at the C-terminus, and a half-life extending group. The analogs of the present invention are soluble at pH around 6 and 7. The present invention also relates to pharmaceutical compositions containing such PYY analogs and pharmaceutical uses of the analogs.

Description

[Technical field]

[0001] The present invention relates to PYY analogues that are neuropeptide Y2 (NPY2) receptor agonists and their medical uses in the treatment and / or prevention of various diseases, conditions, or disorders, such as the treatment and / or prevention of excessive food intake, excess weight, obesity, metabolic diseases, and other conditions or disorders associated with excess weight or obesity, such as diabetes and cardiovascular disease. [Background technology]

[0002] Overweight and obesity are defined as abnormal or excessive body fat accumulation that represents a risk to health. In this regard, overweight and obesity are major risk factors for several chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer. According to the WHO, overweight and obesity are no longer considered to be a problem limited to high-income countries, but are now increasing dramatically in low- and middle-income countries. The WHO Global Health Observatory indicates that in 2016, 39% of women and men aged 18 years and older were overweight, while 11% of men and 15% of women were obese. Despite years of efforts, the number of overweight and obese patients is still increasing. First-line treatments for overweight and obese patients include diet and exercise, but are often not fully effective. Second-line treatments are bariatric surgery and pharmacotherapy. Available pharmacological treatments appear to lack efficacy and / or safety, and only a limited number of approved treatments are available in the United States and Europe. Thus, there remains a high medical need for more effective and safer treatment options. NPY (neuropeptide Y, SEQ ID NO:1-human sequence), PYY (peptide YY, SEQ ID NO:2-human sequence), and PP (pancreatic polypeptide, SEQ ID NO:3-human sequence) are naturally secreted homologous 36 amino acid C-terminally amidated peptides that belong to the PP-fold family of peptides. Sequence of hPYY(3-36): Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr (SEQ ID NO: 4)

[0003] PYY is cleaved by dipeptidyl peptidase IV (DPP IV) to PYY(3-36). Compared with PYY(1-36), PYY(3-36) exhibits increased selectivity for the neuropeptide Y2 receptor over the neuropeptide Y1, Y4, and Y5 receptors, but retains some Y1 and Y5 affinity. PYY or PYY(3-36) is thought to exert an antifeedant effect via activation of the neuropeptide Y2 receptor (Inhibition of Food Intake in Obese Subjects by Peptide YY 3-36 , N Engl J Med 2003;349;941-8). However, PYY, and even PYY(3-36), exhibits undesirable chemical or physical properties, such as poor stability, a short half-life in the body, and its pharmacological effects, such as its effectiveness as a weight loss agent, appear to be limited. International Publication No. WO2014 / 178018 discloses PYY analogues and their ability to reduce food intake in mice. International Publication Nos. WO2011 / 033068 and WO2011 / 058165 disclose long-acting Y2 receptor agonists. International Publication Nos. WO2015 / 071355, WO2016 / 198682, and WO2020 / 092191 relate to PYY compounds that are selective Y2 receptor agonists. Disclosed are PYY compounds that include covalently attached substituents or modifying groups, also referred to as extension moieties therein. There is a need in the art for further (long-acting) PYY analogues that selectively act on NPY2 receptor.For example, it would be desirable to further increase the solubility of PYY analogues, preferably at around pH 7 and / or pH 6.This would increase the formulation options for ready-to-use application and potentially allow for combination with other (peptide) therapeutics to improve efficacy. The PYY analogues of the present invention have generally been found to be soluble at around pH 6 and pH 7. Summary of the Invention

[0004] In a first aspect, the present invention provides a PYY analogue comprising: i) an alanine at a position corresponding to position 4 of hPYY(3-36); ii) a lysine at a position corresponding to position 7 of hPYY(3-36); iii) the sequence QRY at its C-terminus Including, a half-life extending group is attached to the epsilon amino group of lysine at position 7, or to the epsilon amino group of lysine at positions 6, 10, 11, 14, 17, 21, 22, or 30, or to the carboxylic acid group of the side chain of aspartic acid or glutamic acid at positions 14 or 30; Provides a PYY analogue.

[0005] In some embodiments, the PYY analog is i) an alanine at a position corresponding to position 4 of hPYY(3-36); ii) a lysine at a position corresponding to position 7 of hPYY(3-36); iii) a proline at a position corresponding to position 5 of hPYY(3-36); iv) a glutamine at a position corresponding to position 18 of hPYY(3-36); v) a leucine at a position corresponding to position 24 of hPYY(3-36); vi) an arginine at a position corresponding to position 25 of hPYY(3-36); vii) a histidine at a position corresponding to position 26 of hPYY(3-36); viii) a leucine at a position corresponding to position 31 of hPYY(3-36); ix) the sequence QRY at its C-terminus wherein the half-life extending group is attached to the epsilon amino group of the lysine at position 7, or to the epsilon amino group of the lysine at positions 6, 10, 11, 14, 17, 21, or 22, or to the carboxylic acid group of the side chain of the aspartic acid or glutamic acid at position 14.

[0006] In some embodiments of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C6H6, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl-C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 is OH or NHR 3 where R 3 is hydrogen or C 1-3 is alkyl, Z is an amino acid sequence of formula Ib: Ala-Pro-X6-Lys-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Gln-X19-X20-X 21-X22-X23-Leu-Arg-His-X27-X28-X29-X30-Leu-X32-X33-Gln-Arg-Tyr(Ib) A peptide comprising the formula: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu, Gly, and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, Glu, Ile, Leu, Pro, Gln, and Ser; X12 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X13 is selected from the group consisting of Ala, Glu, Leu, Ser, Gln, Thr, and Pro; X14 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X15 is selected from the group consisting of Ala and Glu; X16 is selected from the group consisting of Ala, Glu, and Lys; X17 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X19 is selected from the group consisting of Ala, Glu, Leu, Arg, Lys, Pro, Ser, and Gln; X20 is selected from the group consisting of Gln and Tyr; X21 is selected from the group consisting of Gln and Tyr; X22 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gly, Leu, Pro, Gln, Ser, Thr, and Val; X27 is selected from the group consisting of Gln and Tyr; X28 is selected from the group consisting of Gln and Tyr; X29 is selected from the group consisting of His, Asn, and Gln; X30 is selected from the group consisting of Trp and Lys; X32 is selected from the group consisting of Gln, Leu, Ser, and Thr; X33 is selected from the group consisting of Lys and Arg; 1 to 3 amino acids among X6, X8 to 17, X19 to X23, and X27 to X32 may be absent; The half-life extending group is attached to the epsilon amino group of the lysine at position 7.

[0007] In some embodiments, the half-life extending group consists of a lipophilic substituent X and a linker U, where the linker U is attached to an amino acid side chain and X is attached to U, and the linker U consists of one, two or three submoieties (U1, U2, U3), where at least one submoiety is Ahx. In some embodiments, the lipophilic substituent X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA), and 19-carboxy-nonadecanoyl, and the linker U is independently selected from the group consisting of Gly, Glu, γ-Glu, ε-Lys, Ser, Ahx, and OEG, or consists of one, two, or three submoieties independently selected from the group consisting of γ-Glu, Ahx, and OEG.

[0008] In some embodiments, the PYY analog is selected from compounds 245-443 described herein. In some embodiments, the PYY analogue is in the form of a salt, preferably a pharma- ceutically acceptable salt form. The present invention further provides compositions comprising the PYY analogs described herein. The present invention further provides PYY analogues for use in methods of medical treatment, such as for use in the treatment of obesity and various obesity-related conditions, diseases, or disorders, such as type 2 diabetes, NAFLD, or NASH. The present invention provides a PYY analogue of the invention for use in a method for treating, preventing or reducing weight gain, promoting weight loss, and / or reducing excess weight. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Terms, definitions and conventions Terms not specifically defined herein shall be given the meaning ordinarily given by one of ordinary skill in the art in light of the present disclosure and the context. However, as used herein, unless otherwise indicated, the following terms have the meanings indicated and follow the following conventions: Throughout this specification, the amino acid positions of the PYY analogues are numbered according to the corresponding positions in native human PYY, the sequence of which is shown above. PYY Analog A PYY analogue is a peptide that contains an amino acid sequence that corresponds to the amino acid sequence of hPYY(3-36). In other words, a PYY analogue is a peptide that is structurally related to PYY and has one or more amino acid residues modified compared to hPYY(3-36). Possible modifications are substitutions, insertions, or deletions of amino acids at specific positions. The PYY analogue of the present invention relates to peptides that retain a certain binding affinity (Ki) to the hNPY2 receptor. The term "PYY analogue" includes the peptide itself, i.e., in its non-ionized state, as well as the peptide in its ionized state (e.g., where one or more side chains of its amino acids are ionized, i.e., (de)protonated). The term "PYY analog" may also refer to a peptide in which a half-life extending group is attached to one or more amino acids of the peptide. In such cases, the side chain of the amino acid has a half-life extending group covalently attached thereto.

[0010] As used herein, the term "pharmaceutically acceptable salt" is intended to refer to a salt that is not harmful to the patient or subject to whom the salt in question is administered. It may suitably be, for example, a salt selected from an acid addition salt and a base salt. As used herein, "pharmaceutically acceptable salt" refers to a derivative of a disclosed analog or compound, in which the parent analog or compound is modified by making an acid or base salt thereof. Examples of acid addition salts include chloride salts, citrate salts, and acetate salts. Examples of base salts include salts in which the cation is an alkali metal cation, e.g., sodium or potassium ion, an alkaline earth metal cation, e.g., calcium or magnesium ion, and a substituted ammonium ion, e.g., N(R 1 )(R 2 )(R 3 )(R 4 ) + Ions of the type (wherein R 1 , R 2 , R 3 , and R 4 are independently typically hydrogen or optionally substituted C 1-6 Other examples of pharma- ceutically acceptable salts include those described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and newer editions thereof), "Encyclopaedia of Pharmaceutical Technology", 3 rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, Vol. 5, No. 1, p. 3177, and in J. Pharm. Sci. 66: 2 (1977).

[0011] The term "agonist", as used in the context of the present invention, refers to a substance that effects activation of a receptor type in question, typically by binding to it (ie, as a ligand). Each embodiment of the present invention described herein may be used alone or in combination with one or more other embodiments of the present invention. Throughout this specification, naturally occurring amino acids are designated by their conventional three letter or one letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.), unless they are referred to by their full name (e.g., alanine, arginine, etc.). Unless otherwise indicated, reference is made to the L-isomer form of the amino acid in question.

[0012] Additional abbreviations are as follows: Hyp: 4-hydroxyproline, e.g., (2S,4R)-4-hydroxyproline [also indicated as (4R)-4-hydroxy-L-proline] γ-Glu: γ-glutamic acid (also referred to as gGlu) "C 1-n The term "alkyl", alone or in combination with other radicals, refers to an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms, where n is an integer selected from 2, 3, 4, 5, or 6. For example, C 1-5 The term -alkyl encompasses the radicals HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-CH-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH(CH)-CH-, HC-CH-CH-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH-, HC-CH-CH(CH)-CH-, and HC-CH-CH(CHCH)-. "C 3-nThe term "cycloalkyl", where n is an integer from 4 to n, alone or in combination with other radicals, refers to a cyclic, saturated, unbranched hydrocarbon radical having 3 to n C atoms. For example, C 3-6 The term -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "C(O)" or "C(=O)" refers to a carbonyl group.

[0013] Compound Nomenclature For example, iVal-APAK(C18DA-gGlu-Ahx)PPEDASPEELQRYYVELRHYYNWLTRQRY-NH2 (In the formula, iVal represents 3-methylbutanoyl (-C(O)CHCH(CH)), C18DA stands for 17-carboxyheptadecanoyl; gGlu represents L-γ-glutamyl connected through its amino group to C18DA and through its γ-carboxy group to Ahx; Ahx represents 6-amino-hexanoyl connected through its amino group to gGlu and through its carboxy group to the ε-amino group of lysine (K). fully defines a PYY analogue of the following structure:

[0014] [ka] Alternatively, the same compound can be defined in the following manner: N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9P,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36).

[0015] The term "treatment" and its grammatical variants (e.g., "treated", "treating", "treating") as used in this context refers to an approach to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, attenuation of the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, alleviation or mitigation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival compared to the expected survival in the absence of treatment. A subject (e.g., a human) in need of treatment may therefore be a subject already suffering from the disease or disorder in question. The term "treatment" includes prevention or reduction of the increase in the severity of a pathological condition or symptom (e.g., weight gain or hyperglycemia) compared to the absence of treatment, and is not necessarily meant to indicate a complete cessation of the associated disease, disorder, or condition.

[0016] The term "prevention" and its grammatical variants (e.g., "prevented", "preventing", "preventing") as used in this context refers to an approach to hinder or prevent the development of a condition, disease, or disorder, or to alter its etiology. Thus, "prevention" can refer to prophylactic or preventive measures. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, the prevention or delay of disease symptoms, progression, or development, whether detectable or undetectable. A subject (e.g., a human) in need of "prevention" may be one who is not yet afflicted with the disease or disorder in question. The term "prevention" includes arresting or delaying the onset of a disease compared to the absence of treatment, and is not necessarily meant to indicate permanent prevention of the associated disease, disorder, or condition.

[0017] Half-life extender As described herein, the half-life extending group is covalently attached to a functional group of the side chain of an amino acid of a PYY analog. The half-life extending group comprises or consists of a lipophilic substituent (X) and, optionally, a linker (U), where one end of the linker U (if present) is attached to the amino acid of the PYY analog and the other end is connected to the lipophilic substituent (-UX). Without wishing to be bound by any particular theory, it is believed that such lipophilic substituents (and other classes of half-life extending moieties) bind to albumin and other plasma components in the bloodstream, thereby protecting the compounds of the invention from renal infiltration and enzymatic degradation, thus potentially enhancing the half-life of the compounds in vivo. Lipophilic substituents may also modulate the efficacy of the compounds as agonists for the NPY2 receptor, or for other receptors in the NPY receptor family.

[0018] The lipophilic substituent X is attached to the linker U via an ester, ether, sulfonyl ester, thioester, amide, amine, triazole or sulfonamide. It will thus be understood that preferably the lipophilic substituent X comprises an acyl group, a sulfonyl group, an alkyne, an azide, an N atom, an O atom or an S atom which form part of an ester, sulfonyl ester, thioester, triazole, amide, amine or sulfonamide. Preferably, the acyl group or the O or N atom in the lipophilic substituent X forms part of an amide or ester together with the linker U. The half-life extending group (and its linker U, if present) is attached to the amino acid residue of the PYY analogue via an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. It will therefore be understood that preferably the half-life extending group (and its linker U, if present) comprises an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom that forms part of an ester, a sulfonyl ester, a thioester, an amide, an amine, or a sulfonamide. Preferably, the acyl group, or the O or N atom in the linker U forms part of an amide or ester with the amino acid residue.

[0019] The lipophilic substituent X may comprise a hydrocarbon chain having 10-24 C atoms, such as 14-22 C atoms, such as 16-20 C atoms. Preferably, it has at least 14 C atoms, preferably 20 or less C atoms. For example, the hydrocarbon chain may comprise 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The hydrocarbon chain may be linear or branched, saturated or unsaturated. Furthermore, the hydrocarbon chain may comprise a functional group, such as a carboxylic acid group, a sulfonic acid group, or a tetrazole group, at the end of the hydrocarbon chain. From the above considerations, it will also be understood that the hydrocarbon chain is preferably substituted with a moiety that forms part of the bond to the amino acid residue of the PYY analogue or to the linker U, such as an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom.

[0020] Most preferably, the hydrocarbon chain is substituted with an acyl group (e.g., for attachment to the linker U), and thus the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, or eicosanoyl group. These hydrocarbon chains substituted with an acyl group at one end may further be functionalized with a carboxylic acid group at the other end of the chain. Examples of functionalized hydrocarbon chains (e.g., lipophilic substituents X) are 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, and 19-carboxy-nonadecanoyl.

[0021] In certain embodiments, the linker moiety U may itself be one, two, three, or more linked submoieties (U 1 , U 2 , U 3In some of these embodiments, the linker may include one or more (e.g., one, two, or three) linked amino acid residues, each of which is independently a residue of any naturally occurring or non-naturally occurring amino acid. For example, the linker may include one, two, or three linked amino acid residues, each of which is independently a residue of any naturally occurring or non-naturally occurring amino acid, such as Gly, Pro, Ala, Val, Leu, Ile, Cys, Phe, Tyr, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Aib, AEA (2-(2-aminoethoxy)acetic acid), Ahx (6-aminohexanoic acid), AEEEA (2-{ 2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetic acid), H2N-dPEG(4)-COOH(15-amino-4,7,10,13-tetraoxa-pentadecanoic acid), H2N-dPEG(6)-COOH(1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oic acid), H2N-dPEG(12)-COOH(1-amino-3,6,9,12,15,18,21,24,27,30,33,36 -dodecaoxanonatriacontan-39-oic acid), OEG-OEG (2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetamido}ethoxy)ethoxy]acetic acid), H-Ebes (3-({2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamoyl)propanoic acid), H-DOOA-DIG-OH (2-[({2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamoyl)methoxy]acetic acid), It may be a residue of H-TTD-DIG-OH (2-{[(3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propyl)carbamoyl]methoxy}acetic acid), H-TTDS-OH (3-[(3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propyl)-carbamoyl]propanoic acid), or 8Ado (i.e., 8-amino-3,6-dioxaoctanoyl, also referred to herein as OEG).

[0022] References to γ-Glu, ε-Lys, and β-Asp refer to amino acid residues participating in the bond via their side chain carboxyl or amine functional groups. Thus, γ-Glu and β-Asp participate in the bond via their alpha amino and side chain carboxyl groups, while ε-Lys participates via its carboxyl and side chain amino groups. In the context of the present invention, γ-Glu, gGlu, and isoGlu are used interchangeably. In certain embodiments, the linker U is selected from one, two, or three independently selected submoieties (U 1 , U 2 , U 3 ) Linkers that include Ahx as a submoiety (e.g., γ-Glu-Ahx, Ahx-γ-Glu, Ahx-Ahx, γ-Glu-γ-Glu-Ahx, Ahx-γ-Glu-γ-Glu) may be preferred. Synthesis of PYY analogues The present invention provides methods for the synthesis of the PYY analogs of the invention. PYY analogs can be produced by standard synthetic methods, including standard solid-phase or solution-phase methods. Peptides are assembled, either stepwise or by combining fragments, and optionally isolated and purified to obtain the final peptide product. Examples of synthesis are described in Fields, GB et al., "Principles and Practice of Solid-Phase Peptide Synthesis" in Synthetic Peptides, Grant GA (ed.), Oxford University Press (2 nd This paper has been described in numerous publications, including the International Journal of Clinical Chemistry (IJCCH), Vol. 1, No. 1, 2002.

[0023] Embodiment In a first aspect, the present invention provides a PYY analogue comprising: i) an alanine at a position corresponding to position 4 of hPYY(3-36); ii) a lysine at a position corresponding to position 7 of hPYY(3-36); iii) the sequence QRY at its C-terminus Including, a half-life extending group is attached to the epsilon amino group of lysine at position 7, or to the epsilon amino group of lysine at positions 6, 10, 11, 14, 17, 21, 22, or 30, or to the carboxylic acid group of the side chain of aspartic acid or glutamic acid at positions 14 or 30; Provides a PYY analogue. In some embodiments, the PYY analog contains a proline at the position corresponding to position 5 of hPYY(3-36). In some embodiments, the PYY analog contains a glutamine at a position corresponding to position 18 of hPYY(3-36).

[0024] In some embodiments, the PYY analog contains a leucine at a position corresponding to position 24 of hPYY(3-36). In some embodiments, the PYY analog contains an arginine at a position corresponding to position 25 of hPYY(3-36). In some embodiments, the PYY analog contains a histidine at a position corresponding to position 26 of hPYY(3-36). In some embodiments, the PYY analog contains a leucine at a position corresponding to position 31 of hPYY(3-36). In some embodiments, the PYY analog contains an arginine or lysine at a position corresponding to position 33 of hPYY(3-36). In some embodiments, the PYY analog has a half-life extending group attached to the epsilon amino group of the lysine at the 7 position. In some embodiments of the invention, the half-life extending group consists of a lipophilic substituent X and a linker U, said linker U being attached to an amino acid side chain and said X being attached to U.

[0025] In some embodiments, the linker U consists of one, two, or three submoieties (U1, U2, U3), with at least one submoiety being Ahx. In some embodiments, the PYY analog is i) an alanine at a position corresponding to position 4 of hPYY(3-36); ii) a lysine at a position corresponding to position 7 of hPYY(3-36); iii) a proline at a position corresponding to position 5 of hPYY(3-36); iv) a glutamine at a position corresponding to position 18 of hPYY(3-36); v) a leucine at a position corresponding to position 24 of hPYY(3-36); vi) an arginine at a position corresponding to position 25 of hPYY(3-36); vii) a histidine at a position corresponding to position 26 of hPYY(3-36); viii. a leucine at a position corresponding to position 31 of hPYY(3-36); ix) the sequence QRY at its C-terminus wherein the half-life extending group is attached to the epsilon amino group of the lysine at position 7, or to the epsilon amino group of the lysine at positions 6, 10, 11, 14, 17, 21, or 22, or to the carboxylic acid group of the side chain of the aspartic acid or glutamic acid at position 14.

[0026] In some embodiments, the PYY analog contains an arginine at a position corresponding to position 33 of hPYY(3-36). In some embodiments, the PYY analog contains a tryptophan or lysine at the position corresponding to position 30 of hPYY(3-36). In some embodiments, the PYY analog contains a glutamine or tyrosine at a position corresponding to position 28 of hPYY(3-36). In some embodiments, the PYY analog contains a glutamine or tyrosine at a position corresponding to position 27 of hPYY(3-36). In some embodiments, the PYY analog contains a glutamine or tyrosine at a position corresponding to position 21 of hPYY(3-36). In some embodiments, the PYY analog contains a glutamine or tyrosine at the position corresponding to position 20 of hPYY(3-36). In some embodiments, the PYY analog contains an alanine or glutamic acid at the position corresponding to position 15 of hPYY(3-36). In some embodiments, the PYY analog contains an alanine or glutamic acid at the position corresponding to position 10 of hPYY(3-36).

[0027] In some embodiments, the PYY analog contains an alanine or proline at the position corresponding to position 8 of hPYY(3-36). In some embodiments, the PYY analog contains an alanine or glutamic acid at the position corresponding to position 6 of hPYY(3-36). In some embodiments, the PYY analog has a half-life extending group attached to the epsilon amino group of the lysine at the 7 position. In some embodiments, the PYY analog is i) an alanine at a position corresponding to position 4 of hPYY(3-36); iii) a proline at a position corresponding to position 5 of hPYY(3-36); iv) alanine or glutamic acid at the position corresponding to position 6 of hPYY(3-36); v) a lysine at a position corresponding to position 7 of hPYY(3-36); vi) alanine or proline at the position corresponding to position 8 of hPYY(3-36); vii) alanine or glutamic acid at the position corresponding to position 10 of hPYY(3-36); viii) alanine or glutamic acid at a position corresponding to position 15 of hPYY(3-36); ix) a glutamine at a position corresponding to position 18 of hPYY(3-36); x) a glutamine or tyrosine at a position corresponding to position 20 of hPYY(3-36); xi) glutamine or tyrosine at a position corresponding to position 21 of hPYY(3-36); xii) a leucine at a position corresponding to position 24 of hPYY(3-36); xiii) an arginine at a position corresponding to position 25 of hPYY(3-36); xiv) a histidine at a position corresponding to position 26 of hPYY(3-36); xv) glutamine or tyrosine at a position corresponding to position 27 of hPYY(3-36); xvi) glutamine or tyrosine at a position corresponding to position 28 of hPYY(3-36); xvii) tryptophan or lysine at a position corresponding to position 30 of hPYY(3-36) xviii) a leucine at a position corresponding to position 31 of hPYY(3-36); xix) the sequence RQRY at its C-terminus wherein the half-life extending group is attached to the epsilon amino group of the lysine at position 7, or to the epsilon amino group of the lysine at positions 11, 14, 17, or 22, or to the carboxylic acid group of the side chain of the aspartic acid or glutamic acid at position 14. In some embodiments, exactly one half-life extending group is attached to the PYY analogue, said half-life extending group being attached to the epsilon amino group of the lysine at position 7.

[0028] In some embodiments according to the previous paragraph, the linker U of the half-life extending group is composed of one, two, or three submoieties (U1, U2, U3), and at least one submoiety is Ahx.

[0029] In some embodiments of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 is hydrogen, -C(O)C 1-6Alkyl, -C(O)C6H6, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl-C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 is OH or NHR 3 where R 3 is hydrogen or C 1-3 is alkyl, Z is an amino acid sequence of formula Ib: Ala-Pro-X6-Lys-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Gln-X19-X20-X 21-X22-X23-Leu-Arg-His-X27-X28-X29-X30-Leu-X32-X33-Gln-Arg-Tyr(Ib) A peptide comprising the formula: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu, Gly, and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, Glu, Ile, Leu, Pro, Gln, and Ser; X12 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X13 is selected from the group consisting of Ala, Glu, Leu, Ser, Gln, Thr, and Pro; X14 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X15 is selected from the group consisting of Ala and Glu; X16 is selected from the group consisting of Ala, Glu, and Lys; X17 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X19 is selected from the group consisting of Ala, Glu, Leu, Arg, Lys, Pro, Ser, and Gln; X20 is selected from the group consisting of Gln and Tyr; X21 is selected from the group consisting of Gln and Tyr; X22 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gly, Leu, Pro, Gln, Ser, Thr, and Val; X27 is selected from the group consisting of Gln and Tyr; X28 is selected from the group consisting of Gln and Tyr; X29 is selected from the group consisting of His, Asn, and Gln; X30 is selected from the group consisting of Trp and Lys; X32 is selected from the group consisting of Gln, Leu, Ser, and Thr; X33 is selected from the group consisting of Lys and Arg; 1 to 3 amino acids among X6, X8 to 17, X19 to X23, and X27 to X32 may be absent; The half-life extending group is attached to the epsilon amino group of the lysine at position 7.

[0030] In a further embodiment, the PYY analogue is according to the previous embodiment, wherein one of X6, X8-17, X19-X23, and X27-X32 is absent. In a further embodiment, the PYY analogue is according to the previous embodiment, wherein any of X6, X8 to X17, X19 to X23, and X27 to X32 are not absent. In a further embodiment, R 1 is -C(O)C 1-4 Alkyl, -C(O)C 3-5 Cycloalkyl, -C(O)C 1-3 Alkyl-C 3-4 Cycloalkyl, C 1-4 Alkyl or C 1-3 Alkyl-C3-4 It is cycloalkyl. In a further embodiment, R 1 are -C(O)CH2CH(CH3)2, -C(O)CH2-cyclobutyl, -C(O)CH2-cyclopropyl. PYY analogs of the invention having an alanine at position 4 and a lysine at position 7 have generally been found to be soluble at around pH 6 and pH 7.

[0031] Peptide therapeutics are usually provided as pharmaceutical liquid formulations in pre-filled ready-to-use injection devices.These peptide formulations for subcutaneous administration have limited application volume.Therefore, good solubility of peptide is a requirement for application in ready-to-use injection devices. Further important aspects are the long-term stability and solubility of the peptide in liquid formulations. A fundamentally important property for physical stability is inherent solubility (at a given pH value).

[0032] A broad pH range (solubility window) in which peptide therapeutics are reasonably soluble is also desirable, as it allows for more flexibility in the development of pharmaceutical formulations. This flexibility may be desirable because other factors, such as chemical stability, are also pH-dependent. In general, peptide formulations at approximately pH 6.0 are believed to exhibit reduced oxidation rates (e.g., Cys oxidation, disulfide bridges, and oxidation of Trp residues), deamidation rates, and aspartic acid isomerization rates compared to formulations at pH 7. For example, Bak et al. (A. Bak, D. Leung, SE Barrett, S. Forster, ED Minnihan, AW Leithead, J. Cunningham, N. Toussaint, LS Crocker, The AAPS Journal, Vol. 17, No. 1, 2015, p. 144 - 155) state that lower pH generally reduces the propensity for oxidation, and suggest maintaining a pH below 7 as a strategy to mitigate the risks associated with oxidation. Therefore, where chemical stability of peptides containing asparagine, aspartic acid or glutamine, tryptophan, cysteine, or methionine is an issue, it may be desirable to have the option of formulating at approximately pH 6.

[0033] The efficacy of obesity treatment drugs is limited. However, efficacy can be improved by combining different therapeutic principles. NPY2 receptor agonists are considered to be promising partners for combination with other weight-reducing treatment drugs. For example, NPY2 receptor agonists show enhanced efficacy of weight-reducing together with GLP-1 receptor agonists (e.g., International Publication Nos. WO2005 / 077072, WO2014 / 178018, WO2018 / 081370) or amylin (e.g., International Publication Nos. WO2006 / 066024, WO2009 / 064298). Natural amylin and many amylin (or calcitonin) analogs contain disulfide bridges. Thus, fixed dose combinations of PYY analogs and amylin analogs may benefit from the opportunity to formulate at lower pH, where the disulfide bridges of the amylin analogs may exhibit improved stability (e.g., due to reduced intramolecular disulfide bond cross-linking reactions). This indicates that the advantage of being able to formulate at a pH below 7 may not only be due to the high stability of the NPY analogs, but also that the combination partners may exhibit improved stability (or solubility) at low pH. Therefore, it is highly desirable to identify NPY2 receptor agonists with a broad solubility window in order to enable co-formulation development with a wide range of partners.

[0034] However, increased solubility should not come at the cost of reduced activity or potency. Surprisingly, alanine at position 4 has been found to increase solubility around pH 6 in the PYY analogs of the invention with no or only minor negative impact on activity or potency or other important properties (e.g., chemical or physical stability). A long in vivo half-life is also a beneficial property of an agent for reducing food intake in overweight or obese patients. Compounds with a long-acting profile (compared to the very short in vivo half-life of native (human) PYY) that reduces the frequency of administration are desirable. In one embodiment, the present invention relates to PYY analogs that are NPY2 receptor agonists. In one aspect, the present invention relates to PYY analogs that exhibit selectivity for the NPY receptor subtype Y2 over the Y receptor subtypes Y1, Y4, and Y5. In one aspect, the invention relates to PYY analogs that have an extended half-life, e.g., a half-life longer than the half-life of hPYY(3-36), e.g., the PYY analogs of the invention are suitable for once-weekly administration. Additionally or alternatively, the present invention relates to PYY analogues that have high chemical and / or physical stability, for example around pH 6 or pH 7.

[0035] Further, more specific embodiments are defined below. In one embodiment of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 and R 2 is as defined above, Z is an amino acid sequence of formula Ib, the half-life extending group is attached to the epsilon amino group of the lysine at position 7 and consists of a lipophilic substituent X and a linker U; The linker U is attached to an amino acid side chain, and X is attached to U, and the linker U consists of one, two or three sub-moieties (U1, U2, U3), with at least one sub-moiety being Ahx.

[0036] In a further embodiment of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C6H6, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl-C 3-6Cycloalkyl, or C 1-6 Alkyl or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 is OH or NHR 3 where R 3 is hydrogen or C 1-3 is alkyl, Z is an amino acid sequence of formula IIb: Ala-Pro-X6-Lys-X8-X9-X10-X11-Ala-X13-X14-Glu-Glu-X17-Gln-X19-Tyr-Tyr-X22-X23-Leu-Arg-His-Tyr-Tyr-X29-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IIb) where: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X14 is selected from the group consisting of Ala, Glu, and Pro; X17 is selected from the group consisting of Ala, Ile, Leu, Ser, and Thr; X19 is selected from the group consisting of Arg and Gln; X22 is selected from the group consisting of Ile, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gln, and Ser; X29 is selected from the group consisting of Asn and Gln; The half-life extending group is attached to the epsilon amino group of the lysine at position 7.

[0037] According to a further embodiment, up to three residues of X6 to X23 are Ala. According to a further embodiment, at least four residues of X6 to X23 are Glu.In a further embodiment, at least four residues of X6, X9, X10, X13, X15, X16 and X23 are Glu. According to a further embodiment, up to three residues among X6 to X23 are Ala and at least four residues among X6, X9, X10, X13, X15, X16 and X23 are Glu. In one embodiment of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 and R 2 is as defined above, Z is an amino acid sequence of formula IIb, the half-life extending group is attached to the epsilon amino group of the lysine at position 7 and consists of a lipophilic substituent X and a linker U; The linker U is attached to an amino acid side chain, and X is attached to U, and the linker U consists of one, two or three sub-moieties (U1, U2, U3), with at least one sub-moiety being Ahx.

[0038] In some embodiments of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C6H6, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl-C 3-6 Cycloalkyl, or C 1-6 Alkyl or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 is OH or NHR 3 where R 3 is hydrogen or C 1-3is alkyl, Z is an amino acid sequence of formula IIIb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-Tyr-X21-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IIIb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu, Gly, and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, Glu, and Pro; X12 is selected from the group consisting of Ala and Ser; X13 is selected from the group consisting of Ala, Glu, Ser, Thr, and Pro; X14 is selected from the group consisting of Ala, Glu, and Pro; X15 is selected from the group consisting of Ala and Glu; X16 is selected from the group consisting of Ala and Glu; X17 is selected from the group consisting of Ile, Leu, Thr, and Val; X18 is selected from the group consisting of Glu and Gln; X19 is selected from the group consisting of Ala, Glu, Arg, Lys, and Gln; X21 is selected from the group consisting of Glu and Tyr; X22 is selected from the group consisting of He and Val; X23 is selected from the group consisting of Ala, Glu, Ser, and Thr; The half-life extending group is attached to the epsilon amino group of the lysine at position 7.

[0039] In a further embodiment, Z is the amino acid sequence of formula IVb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-Ala-X13-Pro-Glu-Glu-X17-Gln-Arg-Tyr-Tyr-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IVb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X17 is selected from the group consisting of Ile and Leu; X22 is selected from the group consisting of He and Val; X23 is selected from the group consisting of Ala and Ser.

[0040] In one embodiment of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 and R 2 is as defined above, Z is an amino acid sequence of formula IVb, the half-life extending group is attached to the epsilon amino group of the lysine at position 7 and consists of a lipophilic substituent X and a linker U; The linker U is attached to an amino acid side chain, and X is attached to U, and the linker U consists of one, two or three sub-moieties (U1, U2, U3), with at least one sub-moiety being Ahx.

[0041] In a further embodiment, the PYY analog is a compound according to Formula Ib, IIb, IIIb, or IVb, wherein up to three residues, X6 through X23, are Ala. In a further embodiment, the PYY analog is a compound according to Formula Ib, IIb, IIIb, or IVb, wherein at least four of residues X6, X9, X10, X13, X15, X16, and X23 are Glu. In a further embodiment, R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, or C 1-6 It is an alkyl. In a further embodiment, R 1 is hydrogen or C(O)C 1-6 It is an alkyl. In a further embodiment, R 1 is hydrogen or C(O)C 1-4 It is an alkyl. In a more specific embodiment, R 1 is -C(O)CHCH(CH). In a more specific embodiment, R 2 is NH2.

[0042] In some embodiments of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 and R 2 is defined as any of the above definitions, and Z is as defined in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] an amino acid sequence selected from The half-life extending group is attached to the epsilon amino group of lysine at position 7, or to the epsilon amino group of lysine at positions 6, 10, 11, 14, 17, 21, or 22, or to the carboxylic acid group of the side chain of aspartic acid or glutamic acid at position 14.

[0043] In one embodiment of the invention, the PYY analog has the formula: R 1 -ZR 2 wherein R 1 and R 2 is as defined above, Z is an amino acid sequence selected from Table 1; the half-life extending group is attached to the epsilon amino group of the lysine at position 7 and consists of a lipophilic substituent X and a linker U; The linker U is attached to an amino acid side chain, and X is attached to U, and the linker U consists of one, two or three sub-moieties (U1, U2, U3), with at least one sub-moiety being Ahx.

[0044] In some embodiments, the lipophilic substituent X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA), and 19-carboxy-nonadecanoyl. In some embodiments, the linker U is independently selected from the group consisting of Gly, Glu, γ-Glu, ε-Lys, Ser, Ahx, and OEG, or is independently selected from the group consisting of γ-Glu, Ahx, and OEG, and is selected from one, two, or three submoieties (U 1 , U 2 , U 3 )

[0045] In some embodiments, the linker U comprises one or more Ahx as (sub)moieties. In certain embodiments, the linker U is selected from the group consisting of γ-Glu, γ-Glu-γ-Glu, γ-Glu-OEG, OEG-γ-Glu, γ-Glu-Ahx, Ahx-γ-Glu, OEG-OEG, Ahx-Ahx, γ-Glu-γ-Glu-OEG, OEG-γ-Glu-γ-Glu, γ-Glu-γ-Glu-Ahx, Ahx-γ-Glu-γ-Glu, γ-Glu-OEG-OEG, OEG-OEG- γ-Glu, γ-Glu-Ahx-Ahx, and Ahx-Ahx-γ-Glu. In certain embodiments, the linker U is selected from the group consisting of γ-Glu-Ahx, Ahx-γ-Glu, Ahx-Ahx, γ-Glu-γ-Glu-Ahx, Ahx-γ-Glu-γ-Glu, γ-Glu-Ahx-Ahx, and Ahx-Ahx-γ-Glu.

[0046] In a specific embodiment, the half-life extending group is C18DA-γ-Glu-Ahx-, i.e. [ka] It is. In some embodiments of the invention, the PYY analog is a compound selected from the group consisting of Compound 1 to Compound 199, as defined below. In some embodiments, the PYY analog has up to 15 amino acid modifications compared to hPYY(3-36).

[0047] In some embodiments, the PYY analog has up to 14 amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has up to 13 amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has up to 12 amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has up to 11 amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 7 and 15 (i.e., 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid modifications compared to hPYY(3-36). In some embodiments, the PYY analog has between 8 and 14 (ie, 8, 9, 10, 11, 12, 13, or 14) amino acid alterations compared to hPYY(3-36).

[0048] In some embodiments, the PYY analog has between 5 and 13 (i.e., 5, 6, 7, 8, 9, 10, 11, 12, or 13) amino acid modifications compared to hPYY(3-36). In some embodiments, the PYY analog has between 7 and 13 (ie, 7, 8, 9, 10, 11, 12, or 13) amino acid modifications compared to hPYY(3-36). In some embodiments, the PYY analog has between 8 and 13 (ie, 8, 9, 10, 11, 12, or 13) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 9 and 13 (ie, 9, 10, 11, 12, or 13) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 10 and 13 (ie, 10, 11, 12, or 13) amino acid alterations compared to hPYY(3-36).

[0049] In some embodiments, the PYY analog has between 8 and 12 (ie, 8, 9, 10, 11, or 12) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 9 and 12 (ie, 9, 10, 11, or 12) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 10 and 12 (ie, 10, 11, or 12) amino acid modifications compared to hPYY(3-36). In some embodiments, the PYY analog has 11 to 12 (ie, 11 or 12) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analog has between 9 and 11 (ie, 9, 10, or 11) amino acid alterations compared to hPYY(3-36). In some embodiments, the PYY analogues or compounds of the above embodiments are in the form of a salt, preferably a pharma- ceutically acceptable salt. The PYY analogs of the present invention are capable of binding to the human NPY2 receptor (hNPY2-R).

[0050] Binding to biological receptors can be measured by suitable assays known in the art. For example, binding of PYY analogs to NPY2 receptors can be assessed by the radioligand binding competition assay described in Example 1 below. In some embodiments of the compounds of the present invention, the binding affinity (Ki) for the hNPY2 receptor is less than 100 nM (eg, 0.01 to 100 nM). In some embodiments of the compounds of the present invention, the binding affinity (Ki) for the hNPY2 receptor is less than 50 nM (eg, 0.01 to 50 nM). In some embodiments of the compounds of the present invention, the binding affinity (Ki) for the hNPY2 receptor is less than 10 nM (eg, 0.01 to 10 nM). In some embodiments of the compounds of the present invention, the binding affinity (Ki) for the hNPY2 receptor is less than 5 nM (eg, 0.01 to 5 nM). In some embodiments of the compounds of the present invention, the binding affinity (Ki) for the hNPY2 receptor is less than 2 nM (eg, 0.01 to 2 nM). The PYY analogs of the present invention activate the human NPY2 receptor, ie, are NPY2 agonists.

[0051] Generally, it is preferred to use biological assays that measure the intracellular signal transduction caused by the binding of compounds to the relevant receptors.The activation of NPY2 receptor by the compounds of the present invention (which behave as agonists of the receptor) reduces the cAMP concentration, which affects intracellular signal transduction pathways.Therefore, the reduction of cAMP in cells expressing the receptor or any other suitable parameter can be used to monitor the agonist activity on the receptor.Those skilled in the art will recognize suitable assay formats, examples of which are described below. EC 50 The EC value can be used as a numerical measure of agonist potency at a given receptor. 50 The value is a measure of the concentration of compound required to achieve half of the compound's maximal activity in a particular assay, such as the assay described in Example 2 below. In some embodiments of the compounds of the present invention, the EC 50 is less than 100 nM (for example, 0.001 to 100 nM). In some embodiments of the compounds of the present invention, the EC 50 is less than 50 nM (for example, 0.001 to 50 nM). In some embodiments of the compounds of the present invention, the EC 50 is less than 10 nM (for example, 0.001 to 10 nM). In some embodiments of the compounds of the present invention, the EC 50 is less than 5 nM (for example, 0.001 to 5 nM). In some embodiments of the compounds of the present invention, the EC 50 is less than 2 nM (for example, 0.001 to 2 nM).

[0052] As mentioned above, the PYY analogs or compounds of the present invention are generally soluble at around pH 7 and 6. There are several techniques known to those skilled in the art for determining solubility. One such experiment is described in Example 3 below. When specific solubility is provided herein in mg / ml, it refers to the solubility determination in Example 3. In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 1.0 mg / ml at about pH 6 (eg, pH 6.1±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 3.0 mg / ml at about pH 6 (eg, pH 6.1±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 5.0 mg / ml at about pH 6 (eg, pH 6.1±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is 7.0 mg / ml or greater at about pH 6 (eg, pH 6.1±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is 8.0 mg / ml or greater at about pH 6 (eg, pH 6.1±0.2).

[0053] In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 1.0 mg / ml at around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 5.0 mg / ml at around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 7.0 mg / ml at about pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is 8.0 mg / ml or greater at around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 1.0 mg / ml at around pH 6 (eg, pH 6.1±0.2) and around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 3.0 mg / ml at around pH 6 (eg, pH 6.1±0.2) and around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 5.0 mg / ml at around pH 6 (eg, pH 6.1±0.2) and around pH 7 (eg, pH 6.8±0.2). In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 6.0 mg / ml at around pH 6 (eg, pH 6.1±0.2) and around pH 7 (eg, pH 6.8±0.2).

[0054] In some embodiments, the solubility of a PYY analog or compound of the invention is greater than 7.0 mg / ml at around pH 6 (eg, pH 6.1±0.2) and around pH 7 (eg, pH 6.8±0.2). In some embodiments, the PYY analogs or compounds of the invention have favorable pharmacokinetic properties. In this regard, in some embodiments of the invention, the in vivo half-life of the PYY analogs or compounds is at least 3 hours in mice (NMRI mice, see measurements described in Example 5). In some embodiments, the in vivo half-life is at least 5 hours in mice. In some embodiments, the in vivo half-life is at least 7 hours in mice. In some embodiments, the in vivo half-life is at least 10 hours in mice. The present invention further provides a composition comprising the PYY analogue described above. The composition may be a pharmaceutical composition and may include a pharma- ceutically acceptable carrier, excipient, or vehicle. The present invention further provides methods for the synthesis of the above-mentioned PYY analogues, which may comprise the steps of synthesizing the peptide by solid-phase or liquid phase techniques, and optionally isolating and / or purifying the final product.

[0055] Treatment Method The present invention is directed to PYY analogues or compounds as described in the above embodiments, which are useful in the prevention and / or treatment of diseases and / or conditions associated with or modulated by NPY2 receptor activity, including, but not limited to, the treatment and / or prevention of obesity and various obesity-related conditions, diseases, or comorbidities, such as type 2 diabetes and NASH (non-alcoholic steatohepatitis).

[0056] The compounds described herein are useful, inter alia, for preventing weight gain or promoting weight loss. "Preventing" refers to prevention or reduction compared to no treatment, and does not necessarily refer to a complete cessation of weight gain. The peptides may result in a reduction in food intake and / or an increase in energy expenditure, may have beneficial effects on glucose control and / or circulating cholesterol levels, may lower circulating LDL levels, and may increase the HDL / LDL ratio. Thus, the compounds of the present invention may be used for the direct or indirect treatment of any condition caused or characterized by excess weight, such as the treatment and / or prevention of obesity, morbid obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-related sleep apnea. They may also be used to prevent or treat conditions such as obesity-related co-comorbidities caused by or characterized by inadequate glucose control or dyslipidemia (e.g., elevated LDL levels or reduced HDL / LDL ratios), type 2 diabetes, metabolic syndrome, hypertension, atherogenic dyslipidemia, and cardiovascular diseases such as atherosclerosis, coronary heart disease, peripheral arterial disease, stroke, or microvascular disease, as well as cancer. Their effects in these diseases may be the result of or associated with their effects on body weight, or may be independent thereof.

[0057] As mentioned above, the PYY analogs or compounds according to the above embodiments are useful for reducing food intake, promoting weight loss, and preventing or reducing weight gain. As a result, they can be used to treat various conditions, diseases, or disorders in a subject, including, but not limited to, obesity and various obesity-related conditions, diseases, or comorbidities, such as, but not limited to, type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, fatty liver, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and cancer. The subject may suffer from obesity accompanied by at least one weight-related comorbid condition, such as, type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, fatty liver, NAFLD, and NASH. It will be appreciated that the PYY analogs can thus be administered to a subject suffering from a condition or disease characterized by inadequate appetite control or otherwise overeating, such as binge eating disorder and Prader-Willi syndrome. It will be apparent that the present analogues may be used to treat a combination of the conditions or diseases described. Thus, the present invention provides PYY analogues for use in methods of medical treatment, e.g., for treating, preventing or reducing weight gain, promoting weight loss, and / or reducing excess weight. Treatment can be accomplished, for example, by control of appetite, diet, food intake, caloric intake, and / or energy expenditure.

[0058] The present invention also provides the PYY analogs of the present invention for use in methods for treating obesity and related diseases, disorders, and health conditions, including but not limited to morbid obesity, pre-surgical obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-related sleep apnea and respiratory problems, cartilage degeneration, osteoarthritis, and reproductive health complications due to obesity or excess weight, such as infertility.The subject may suffer from obesity accompanied by at least one weight-related comorbidity, such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, cancer, fatty liver, NAFLD, and NASH. The present invention also provides a PYY analogue of the invention for use in a method of prevention or treatment of the above-mentioned conditions or diseases. Thus, the present invention relates to a PYY analogue or compound according to the above-mentioned embodiments for use as a medicament. Furthermore, the present invention relates to the use of a PYY analogue or compound according to the above-mentioned embodiments for the treatment and / or prevention of diseases and / or conditions associated with or modulated by NPY2 receptor activation.

[0059] Furthermore, the present invention relates to the use of a PYY analogue or compound according to the above-mentioned embodiments for the treatment and / or prevention of obesity and various obesity-related conditions, diseases or complications, such as type 2 diabetes and NASH (non-alcoholic steatohepatitis), as well as others mentioned above. In a further aspect, the present invention relates to the use of a PYY analogue or compound according to the above-mentioned embodiments for the preparation of a medicament for the treatment and / or prevention of the above-mentioned diseases and conditions. In a further aspect, the present invention relates to a method for the treatment or prevention of the above mentioned diseases and conditions, comprising administering to a human an effective amount of a PYY analogue or compound according to the above mentioned embodiments. The weekly applied dose range of the compounds of general formula 1 is usually, for humans, 0.01 to 100 mg (subcutaneous administration). The actual pharmacologic effective amount or therapeutic dosage will usually depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the compound will be administered in a dosage and manner that allows delivery of a pharmacologic effective amount based on the patient's unique condition. Combination therapy The PYY analogs of the invention may be administered as part of a combination therapy with another active agent for the treatment of the disease or disorder in question, such as an anti-obesity agent, an anti-diabetic agent, an agent for the treatment of metabolic syndrome, an anti-dyslipidemic agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent. In such cases, the two active agents may be provided together or separately, for example as components in the same pharmaceutical composition or formulation, or as separate formulations.

[0060] Thus, the peptides of the present invention can be used in combination with known types of anti-obesity agents, such as GIP or GLP-1 receptor agonists (including GLP-1 or GLP-1 analogues), exendin-4 or exendin-4 analogues, any other GLP-1 receptor agonists, such as liraglutide (Saxenda™), semaglutide, dulaglutide, albiglutide, MK-8521, or glucagon-GLP-1 dual agonists (e.g., HM-12525, , SAR-425899, MEDI-0382, NN-9277, or International Publication Nos. WO2008 / 101017, WO2008 / 152403, WO2010 / 070252, WO2010 / 070253, WO2010 / 070255, WO2010 / 070251, WO2011 / 006497, WO2011 / 160630, WO2011 / 1 60633, WO2013 / 092703, WO2014 / 041195, WO2015 / 055801, WO2015 / 055802, WO2016 / 166289), oxyntomodulin or oxyntomodulin analogs (e.g., TT-401), or GLP-1 / GIP dual agonists (e.g., tirzepatide, or those described in International Publication No. WO2013 / 092703, WO2014 / 041195, WO2015 / 055801, WO2015 / 055802, WO2016 / 166289, WO2013 / 164483), or a GLP-1 / GIP / glucagon triple agonist (e.g., NN-9423, or those described in International Publication Nos. WO2015 / 067716, WO2016 / 198624, WO2017 / 116204, WO2017 / 116205, WO2018 / 100134, WO2018 / 100135).

[0061] The anti-obesity agent can be amylin or an amylin analogue, such as pramlintide, NN-9838, or an amylin (or calcitonin) analogue disclosed in International Publication Nos. WO2012 / 168430, WO2012 / 168431, WO2012 / 168432, WO2015 / 040182, WO2015 / 071229, WO2016 / 146739, WO2018 / 046719, or WO2018 / 172390. Alternatively, the anti-obesity agent can be Orlistat™, Sibutramine™, phentermine, melanin-concentrating hormone receptor 1 antagonists, CCK, leptin analogs, GOAT inhibitors, ghrelin receptor antagonists, further neuropeptide Y (NPY) analogs, NPY4 receptor agonists, NPY5 receptor antagonists, cannabinoid receptor 1 antagonists, beta-3 agonists, lipase inhibitors, human islet precursor (proIslet) peptide (HIP), melanocortin receptor 4 agonists, and analogs thereof.

[0062] Additionally, the peptides of the present invention may be used in combination with metformin, sulfonylureas, glinides, DPP-IV inhibitors, glitazones, GLP-1 receptor agonists (including GLP-1 or GLP-1 analogues), exendin-4 or exendin-4 analogues, any other GLP-1 receptor agonist, such as liraglutide (Victoza™), semaglutide, dulaglutide, albiglutide, MK-8521, or Glucagon-GLP-1 dual agonists (e.g., HM-12525, SAR-425899, MEDI-0382, NN-9277, or those described in International Publication Nos. WO2008 / 101017, WO2008 / 152403, WO2010 / 070252, WO2010 / 070253, WO2010 / 070255, WO2010 / 070251, WO2011 / 006497, WO2011 / 160630, WO2011 / 160633, WO2013 / 092703, WO2014 / 041195, WO2015 / 055801, WO2015 / 055802, WO2016 / 166289), oxyntomodulin or an oxyntomodulin analog (e.g., TT-401), or an SGLT2 inhibitor (i.e., sodium - may have some benefit when administered in combination with known types of antidiabetic agents, including but not limited to inhibitors of glucose transport, such as gliflozins, e.g., empagliflozin, canagliflozin, dapagliflozin, or ipragliflozin), GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasiglifam), or insulin or insulin analogues. Examples of suitable insulin analogues include, but are not limited to, Lantus™, Novorapid™, Humalog™, Novomix™, Actraphane™, HM, Levemir™, Degludec™, and Apidra™.Other relevant antidiabetic agents in this regard include GLP-1 receptor agonists such as exenatide (Byetta™ and Bydureon™ exendin-4), and Byetta LAR™, and lixisenatide (Lyxumia™).

[0063] According to a more specific embodiment, the PYY analogues of the present invention comprise: - a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, dulaglutide and albiglutide, or the glucagon-GLP-1 dual agonists described in WO2011 / 006497, WO2014 / 041195, WO2015 / 055801, WO2015 / 055802, WO2016 / 166289, an amylin receptor agonist selected from the group consisting of pramlintide or the amylin analogues disclosed in WO2012 / 168430, WO2012 / 168431, WO2012 / 168432, WO2015 / 040182, WO2016 / 146739 or WO2018 / 046719, It is administered as part of a combination therapy with

[0064] The peptides of the present invention may further be used in combination with drugs targeting cardiovascular diseases, such as drugs for treating hypertension, dyslipidemia, inflammation, and platelet function. Drugs for treating hypertension may be selected from the group including, but not limited to, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, beta blockers, or calcium channel blockers. The peptides of the present invention may still further be used in combination with known types of anti-dyslipidemic agents, including, but not limited to, statins, fibrates, niacin, PSCK9 (proprotein convertase subtilisin / kexin type 9) inhibitors, or cholesterol absorption inhibitors.

[0065] The peptides of the present invention may also be used in combination with known types of proton pump inhibitors (i.e., H2O, H3O4, H4O5, H5O6, H6O7, H7O8, H8O9, H9O10, H9O11, H9O2, H9O3, H9O4, H9O5, H9O6, H9O7, H9O8, H9O9, H9O10, H9O11, H9O12, H9O13, H9O14, H9O15, H9O16, H9O17, H9O18, H9O16, H9O17, H9O18, H9O19, H9O2, H9O15, H9O16, H9O17, H9O18, H9O19 ...9, H9O15, H9O16, H9O17, H9O18, H9O19, H9O19, H9O15, H9O19, H9O15, H9O16, H9O17, H9O18, H9O19, H9O19, H9O15, H9O19, H9O15, H9O16, H9O19, H9O18, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9O19, H9 + / K + -ATPase inhibitors). In addition, with regard to anti-inflammatory treatment, the peptides of the invention Steroids and corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; Nonsteroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (e.g., aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miloprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxypinac, sulindac, thiopi nac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (e.g., acetylsalicylic acid and sulfasalazine), and pyrazolones (e.g., apazone, bezupiperylone, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone), COX It may be beneficial when administered in combination with known types of anti-inflammatory agents, including, but not limited to, II inhibitors, such as rofecoxib and celecoxib, preparations of interferon beta (e.g., interferon beta-1a or interferon beta-1b), and certain other compounds, such as 5-aminosalicylic acid, and their prodrugs and pharmacologic acceptable salts. Yet another aspect of the present invention may be as follows. [1] A PYY analog having the formula: R 1 -ZR 2 wherein R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C 6 H 6 , -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl-C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 But OH or NHR 3 where R 3 is hydrogen or C 1-3 is alkyl, Z is an amino acid sequence of formula Ib: Ala-Pro-X6-Lys-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Gln-X19-X20-X 21-X22-X23-Leu-Arg-His-X27-X28-X29-X30-Leu-X32-X33-Gln-Arg-Tyr(Ib) A peptide comprising the formula: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu, Gly, and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, Glu, Ile, Leu, Pro, Gln, and Ser; X12 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X13 is selected from the group consisting of Ala, Glu, Leu, Ser, Gln, Thr, and Pro; X14 is selected from the group consisting of Ala, Glu, Leu, Pro, Gln, and Ser; X15 is selected from the group consisting of Ala and Glu; X16 is selected from the group consisting of Ala, Glu, and Lys; X17 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X19 is selected from the group consisting of Ala, Glu, Leu, Arg, Lys, Pro, Ser, and Gln; X20 is selected from the group consisting of Gln and Tyr; X21 is selected from the group consisting of Gln and Tyr; X22 is selected from the group consisting of Ala, Glu, Ile, Leu, Pro, Gln, Ser, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gly, Leu, Pro, Gln, Ser, Thr, and Val; X27 is selected from the group consisting of Gln and Tyr; X28 is selected from the group consisting of Gln and Tyr; X29 is selected from the group consisting of His, Asn, and Gln; X30 is selected from the group consisting of Trp and Lys; X32 is selected from the group consisting of Gln, Leu, Ser, and Thr; X33 is selected from the group consisting of Lys and Arg; 1 to 3 amino acids among X6, X8 to 17, X19 to X23, and X27 to X32 may be absent; a half-life extending group is attached to the epsilon amino group of a lysine at position 7; the half-life extending group is comprised of a lipophilic substituent X and a linker U, the linker U is attached to an amino acid side chain, the X is attached to U, the linker U is comprised of one, two or three sub-moieties (U1, U2, U3), at least one sub-moiety is Ahx (6-aminohexanoic acid); PYY analogue. [2] Z is an amino acid sequence of the following formula IIb: Ala-Pro-X6-Lys-X8-X9-X10-X11-Ala-X13-X14-Glu-Glu-X17-Gln-X19-Tyr-Tyr-X22-X23-Leu-Arg-His-Tyr-Tyr-X29-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IIb) where: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X14 is selected from the group consisting of Ala, Glu, and Pro; X17 is selected from the group consisting of Ala, Ile, Leu, Ser, and Thr; X19 is selected from the group consisting of Arg and Gln; X22 is selected from the group consisting of Ile, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gln, and Ser; X29 is selected from the group consisting of Asn and Gln; The PYY analog described in [1] above. [3] Z is an amino acid sequence of the following formula IIIb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-Tyr-X21-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IIIb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu, Gly, and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, Glu, and Pro; X12 is selected from the group consisting of Ala and Ser; X13 is selected from the group consisting of Ala, Glu, Ser, Thr, and Pro; X14 is selected from the group consisting of Ala, Glu, and Pro; X15 is selected from the group consisting of Ala and Glu; X16 is selected from the group consisting of Ala and Glu; X17 is selected from the group consisting of Ile, Leu, Thr, and Val; X18 is selected from the group consisting of Glu and Gln; X19 is selected from the group consisting of Ala, Glu, Arg, Lys, and Gln; X21 is selected from the group consisting of Glu and Tyr; X22 is selected from the group consisting of He and Val; X23 is selected from the group consisting of Ala, Glu, Ser, and Thr; The PYY analog described in [1] above. [4] Z is an amino acid sequence of the following formula IVb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-Ala-X13-Pro-Glu-Glu-X17-Gln-Arg-Tyr-Tyr-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr(IVb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X17 is selected from the group consisting of Ile and Leu; X22 is selected from the group consisting of He and Val; X23 is selected from the group consisting of Ala and Ser; The PYY analog described in [1] above. [5] The PYY analog according to any one of [1] to [4] above, wherein none of X6, X8 to X17, X19 to X23, and X27 to X32 is absent. [6] The PYY analog according to any one of [1] to [5] above, wherein the PYY analog has 7 or more but not more than 15 amino acid modifications compared to hPYY(3-36). [7] The PYY analog according to [1] above, wherein Z is an amino acid sequence selected from Table 1. 〔8〕R 1 But -C(O)CH 2 CH(CH 3 ) 2 , -C(O)CH 2 -Cyclobutyl, and -C(O)CH 2 -cyclopropyl. -cyclopropyl. [9] The PYY analog according to any one of [1] to [8] above, wherein up to three residues of X6 to X23 are Ala.

[10] The PYY analog according to any one of [1] to [9] above, wherein at least four of the residues X6, X9, X10, X13, X15, X16, and X23 are Glu.

[11] The linker U of the half-life extending group is composed of one, two, or three submoieties independently selected from the group consisting of Gly, Glu, γ-Glu, ε-Lys, Ser, Ahx, and OEG, and at least one submoiety is Ahx; X of the half-life extending group is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, and 19-carboxy-nonadecanoyl. The PYY analog according to any one of [1] to

[10] above.

[12] The PYY analog according to any one of [1] to

[11] above, which is a compound selected from the group consisting of Compound 1 to Compound 199.

[13] The PYY analog according to any one of [1] to

[12] above, which is in the form of a salt, preferably a pharma-ceutically acceptable salt.

[14] The PYY analog according to any one of [1] to

[13] above, which has a binding affinity (Ki) for hNPY2R of less than 100 nM.

[15] The PYY analog according to any one of [1] to

[14] above, wherein the solubility of the PYY analog is greater than 1.0 mg / ml at pH 6.

[16] A pharmaceutical composition comprising at least one PYY analog according to any one of [1] to

[15] above, and one or more pharma- ceutically acceptable excipients.

[17] The PYY analogue according to any one of [1] to

[15] above, for use in a method of medical treatment, for example, for use in a method of treating a condition or disease associated with or caused by excess weight or excessive weight gain.

[18] The PYY analogue according to any one of [1] to

[15] above, for use in treating obesity or obesity-related conditions or diseases, such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, and cardiovascular disease.

[19] The PYY analog according to any one of [1] to

[15] above, for use in treating atherogenic dyslipidemia, fatty liver, NAFLD, NASH, renal failure, or atherosclerosis.

[20] The PYY analog described in any one of [1] to

[15] above, for use in the treatment described in any one of

[17] to

[19] above, wherein the PYY analog is administered as part of a combination therapy together with a drug for the treatment of diabetes, obesity, dyslipidemia, or hypertension.

[21] The PYY analogue according to any one of [1] to

[15] above, for use in the treatment according to any one of

[17] to

[19] above, wherein the PYY analogue is administered as part of a combination therapy together with a drug for the treatment of obesity, and the drug for obesity is a GIP or GLP-1 receptor agonist, for example, GLP-1 or a GLP-1 analogue, exendin-4 or an exendin-4 analogue, any other GLP-1 receptor agonist including liraglutide, semaglutide, dulaglutide, or albiglutide, or a glucagon-GLP-1 dual agonist, a GLP-1 / GIP dual agonist, or a GLP-1 / GIP / glucagon triple agonist, or an amylin receptor agonist.

[0066] preparation General Procedure for Solid Phase Synthesis of Peptides All peptides were synthesized by standard Fmoc-based solid-phase peptide chemistry on Tentagel S RAM resin (loading 0.23-0.25 mmol / g, bead size 90 μm) supplied by Iris Biotech GmbH or Rapp Polymere GmbH.

[0067] The following protected amino acids were used: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, F moc-Gln(Trt)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu-OtBu, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmo c-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH. Unless otherwise indicated, L-configuration amino acid building blocks were utilized. Modular half-life extenders were constructed by solid phase peptide synthesis (SPPS) using protected building blocks such as, but not limited to, 18-(tert-butoxy)-18-oxooctadecanoic acid (C18DA(tBu)), 2-[2-[2-[[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonyl-amino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid (Fmoc-OEG-OEG-OH), 2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid (Fmoc-OEG-OH), 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (Fmoc-Ahx), and Fmoc-Glu-OtBu.

[0068] Amino acids, Fmoc-Glu-OtBu, Oxyma, and DIC were purchased from standard suppliers, e.g., Bachem, Novabiochem, ABCR, Iris Biotech GmbH, Sigma-Aldrich. 18-(Tert-butoxy)-18-oxooctadecanoic acid (C18DA(tBu)) was provided by Cool Pharm Ltd. or AstraTech, 2-[2-[2-[[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonyl-amino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid (Fmoc-OEG-OEG-OH) was provided by ABCR GmbH & CO. KG or Iris Biotech GmbH, 2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid (Fmoc-OEG-OH) was provided by Combi Blocks Inc., Iris Biotech GmbH, or Hangzhou APIChem Technology Co., Ltd., and 6 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (Fmoc-Ahx) was purchased from Activate Scientific GmbH, and 3-methylbutanoic acid was provided by Sigma-Aldrich GmbH.

[0069] Assembly of the peptides starting from the C-terminus was achieved by stepwise chain elongation towards the N-terminus according to the respective sequences until the N-terminal capping group was reached. Assembly of the half-life extender was performed after deprotection of the branched amino acid side chains, e.g., Lys(Dde). The PYY analogs were obtained as TFA salts by cleavage / deprotection or HPLC purification. The trifluoroacetate was exchanged by standard procedures, e.g., resin-ion exchange procedures, e.g., as disclosed in Roux, St. et al. J. Pept. Sci. 2008; 14: 354-359.

[0070] Synthesis method 1 (S01) Peptides were synthesized by microwave-assisted solid-phase peptide synthesis (SPPS) on a CEM Liberty Blue Peptide Synthesizer on a 0.25 mmol scale on Tentagel S RAM resin using the Fmoc strategy. Standard coupling of amino acids was carried out using 4 equivalents of appropriately protected amino acid in DMF (0.2 mol / l, 5 ml) or 4 equivalents of Fmoc-Ahx (0.2 mol / l) / Oxyma (0.2 mol / l) in DMF (5 ml), 4 equivalents of Oxyma in DMF (1 mol / l, 1 ml), and 8 equivalents of DIC in DMF (1 mol / l, 2 ml) at 90° C. for 4 min. Fmoc-Arg(Pbf)-OH was coupled twice at 90° C. for 4 min, Fmoc-His(Trt)-OH was coupled twice at 50° C. for 12 min, and Fmoc-Glu-OtBu was coupled four times at 50° C. for 12 min. Fmoc-OEG-OH, Fmoc-OEG-OEG-OH, Fmoc-Ahx, and C18DA(tBu) were coupled twice for 4 min at 90° C. Capping of the N-terminus was achieved by coupling 3-methylbutanoic acid three times for 4 min at 90° C. N α Fmoc deprotection was carried out with 20% piperidine / DMF (10 ml) for 1 min at 90° C. Deprotection of the Lys(Dde) group was carried out twice with 5% hydrazine hydrate (10 ml) in DMF for 3 min at 90° C. The crude product was cleaved on the resin after washing with DCM and drying. Cleavage and deprotection from the resin was carried out with a mixture of 95% TFA / water (10 ml) and triisopropylsilane (250 μl) at 42° C. for 40 min. The crude peptide was precipitated with cold tert-butyl-methyl ether, dissolved in 50% acetonitrile / water and purified by preparative HPLC (P01).

[0071] Purification method 1 (P01) The crude peptide was purified by reversed-phase chromatography using an Agilent preparative HPLC-MS system with a preparative pump G1361A, a diode array detector G1315B, a mass spectrometer G1956B, and a fraction collector CTC PAL IFC. A Waters XSelect CSH Prep C18 column (130 Å, 5 μm, OBD, 30 mm×150 mm) served as the stationary phase. The mobile phase consisted of a gradient of buffer A (0.1% TFA in H2O) and buffer B (0.1% TFA in ACN, gradient: 20-42% over 44 min) at 40° C. with a flow rate of 50 ml / min. Relevant fractions were pooled and lyophilized. The final product was characterized by HPLC-MS analysis (A01).

[0072] Purification method 2 (P02) The crude peptide was purified by reversed-phase HPLC using a Gilson preparative HPLC System with an XSelect CSH Phenyl-Hexyl column (Waters 130 Å, 5 μm, 30 mm×150 mm), preparative pumps (Gilson AP-Mod-250 and Gilson 305), UV / VIS detector (Ecom UV10 DAD 800), and a Gilson fraction collector (GX281). The mobile phase consisted of a gradient of Buffer A (0.1% TFA in HO) and Buffer B (0.1% TFA in ACN, gradient: 22-35% over 66 min) at 40° C. with a flow rate of 50 ml / min. Relevant fractions were analyzed, pooled, and lyophilized. The final product was characterized by UPLC-MS analysis (A01).

[0073] Analysis method 1 (A01) Peptide purity and mass were determined by HPLC-MS analysis on a Kinetex C8 column (Phenomenex, 100 Å, 2.6 μm, 4.6 mm×150 mm) using a Waters Acquity HPLC system equipped with a 3100 Mass Detector. Analysis was performed by gradient elution with Buffer A (0.3% TFA in HO) and Buffer B (0.24% TFA in ACN) at a temperature of 40° C. Details of the gradient and flow rates are summarized in the table below. Retention times and masses were recorded. [Table 2]

[0074] List of abbreviations ACN: Acetonitrile Ahx: 6-aminohexanoic acid Boc: tert-butoxycarbonyl C18DA(tBu): 18-(tert-butoxy)-18-oxooctadecanoic acid DPBS: Dulbecco's phosphate buffered saline DCM: dichloromethane DIC: Diisopropylcarbodiimide DIPEA: Diisopropylethylamine Dde: (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl DMF: N,N-dimethylformamide DODT: 3,6-dioxa-1,8-octanedithiol Fmoc: 9H-fluoren-9-ylmethoxycarbonyl Fmoc-Ahx: 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid Fmoc-OEG-OH: 2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid Fmoc-OEG-OEG-OH: 2-[2-[2-[[2-[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonyl-amino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid HTRF: homogeneous time-resolved fluorescence IBMX: 3-isobutyl-1-methylxanthine iVal: 3-Methylbutanoyl (isovalerianoyl) MRT: Average residence time NMP: 1-methyl-pyrrolidin-2-one Oxyma: 2-Cyano-2-(hydroxyimino)acetic acid ethyl ester OEG: 2-[2-(2-aminoethoxy)ethoxy]acetic acid Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl Rt: retention time RT: room temperature SPPS: Solid Phase Peptide Synthesis tBu: tert-butyl Trt: Trityl TES: Triethylsilane TFA: Trifluoroacetic acid The following compounds were synthesized: All compounds were obtained as TFA salts.

[0075] compound 1 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13E,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4792.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.30min, m / 3:1598.0 m / 4: m / 5:

[0076] compound 2 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.07min, m / 3:1603.8 m / 4: m / 5:

[0077] compound 3 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEADAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4720.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.00min, m / 3:m / 4:1180.9 m / 5:

[0078] compound 4 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.10 min, m / 3:1604.1 m / 4:m / 5:

[0079] compound 5 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,20Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRQYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4717.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.77 min, m / 3:1572.4 m / 4:1180.2 m / 5:

[0080] compound 6 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.50min, m / 3:1592.9 m / 4:m / 5:

[0081] compound 7 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEEIQRYYVSLRHYYNWLTRQRY-NH2

[0082] [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.50min, m / 3: m / 4:1192.2 m / 5:

[0083] compound 8 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12E,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDETPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4882.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.94 min, m / 3:1628.0 m / 4:1221.2 m / 5:

[0084] compound 9 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11Q,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEQATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4837.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.52 min, m / 3:1613.3 m / 4: m / 5:

[0085] compound 10 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,11A,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEAAAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4676.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.46 min, m / 3:1560.1 m / 4:1170.2 m / 5:

[0086] compound 11 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,17I,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEIQRYYISLRHYYNWLTRQRY-NH2 [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.29min, m / 3:1589.8 m / 4: m / 5:

[0087] compound 12 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,19Q,22V,28Y,29H,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQQYYVSLRHYYHWLTRQRY-NH2 Molecular weight (calculated): 4805.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.11 min, m / 3:1603.0 m / 4: m / 5:

[0088] compound 13 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,17T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEETQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4740.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.07min, m / 3:1581.0 m / 4: m / 5:

[0089] compound 14 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.97min, m / 3: m / 4:1195.0 m / 5:

[0090] compound 15 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17I,18Q,19Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQQYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4782.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.28 min, m / 3:1595.5 m / 4: m / 5:

[0091] compound 16 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19K,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQKYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4796.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.32min, m / 3:1600.5 m / 4: m / 5:

[0092] compound 17 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22P,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYPSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4822.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.35min, m / 3:1608.2 m / 4: m / 5:

[0093] compound 18 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.50min, m / 3: m / 4:1199.4 m / 5:

[0094] compound 19 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,14E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATEEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4856.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.92 min, m / 3:1619.1 m / 4:1214.3 m / 5:

[0095] compound 20 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,21Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYQVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4717.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.67 min, m / 3:1572.9 m / 4:1180.1 m / 5:

[0096] compound 21 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4836.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.50min, m / 3: m / 4:1209.8 m / 5:

[0097] compound 22 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12P,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDPTPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4850.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.91 min, m / 3:1616.7 m / 4:1214.2 m / 5:

[0098] compound 23 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEEASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.29min, m / 3:1610.2 m / 4: m / 5:

[0099] compound 24 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12S,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDSSPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.77min, m / 3:1603.1 m / 4: m / 5:

[0100] compound 25 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4780.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.39min, m / 3: m / 4:1195.1 m / 5:

[0101] compound 26 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLTRQRY-NH2

[0102] [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.62 min, m / 3:1590.3 m / 4:1192.1 m / 5:954.2

[0103] compound 27 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17S,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEESQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4826.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.31 min, m / 3:1609.1 m / 4: m / 5:

[0104] compound 28 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDATPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4792.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.46 min, m / 3: m / 4:1198.6 m / 5:

[0105] compound 29 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,12S,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADSSPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4768.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.22 min, m / 3:1589.1 m / 4: m / 5:

[0106] compound 30 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,10A,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPADATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.10min, m / 3: m / 4:1184.1 m / 5:

[0107] compound 31 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19P,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQPYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4765.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.82min, m / 3:1588.5 m / 4: m / 5:

[0108] compound 32 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,27Q,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHQYNWLTRQRY-NH2 Molecular weight (calculated): 4717.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.65 min, m / 3:1573.1 m / 4:1181.1 m / 5:

[0109] compound 33 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13E,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.55min, m / 3:1602.9 m / 4: m / 5:

[0110] compound 34 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,14A,18Q,19Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASAEELQQYYVSLRHYYNWLTRQRY-NH2 [ka] Molecular weight (calculated): 4756.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.86 min, m / 3:1585.9 m / 4:1190.1 m / 5:

[0111] compound 35 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4722.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.03 min, m / 3: m / 4:1181.4 m / 5:

[0112] compound 36 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4722.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.66 min, m / 3:1574.8 m / 4:1181.9 m / 5:

[0113] compound 37 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22T,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYTSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4854.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.90min, m / 3: m / 4:1214.4 m / 5:

[0114] compound 38 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19E,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQEYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4797.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.38min, m / 3:1600.9 m / 4: m / 5:

[0115] compound 39 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,16A,18Q,19E,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEALQEYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4725.3 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.52 min, m / 3:1575.9 m / 4: m / 5:

[0116] compound 40 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,17I,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEIQRYYIALRHYYNWLTRQRY-NH2

[0117] [ka] Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.67min, m / 3:1583.6 m / 4: m / 5:

[0118] compound 41 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22T,28Y,29Q,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYTSLRHYYQWLTRQRY-NH2 Molecular weight (calculated): 4868.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.93min, m / 3: m / 4:1218.3 m / 5:

[0119] compound 42 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11P,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEPATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4806.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.57min, m / 3:1603.0 m / 4: m / 5:

[0120] compound 43 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,11A,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEAAAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4692.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.98 min, m / 3:1565.0 m / 4: m / 5:

[0121] compound 44 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23G,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVGLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.20min, m / 3: m / 4:1199.3 m / 5:

[0122] compound 45 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11I,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEIATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4822.6 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.49min, m / 3:1608.4 m / 4: m / 5:

[0123] compound 46 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYASLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4824.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.52 min, m / 3:1609.4 m / 4:1206.3 m / 5:

[0124] compound 47 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDASPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4762.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.44 min, m / 3: m / 4:1191.2 m / 5:

[0125] compound 48 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13T,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4736.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.10min, m / 3: m / 4:1185.0 m / 5:

[0126] compound 49 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23L,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVLLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4850.6 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.55 min, m / 3: m / 4:1213.1 m / 5:

[0127] compound 50 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4858.1 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.00min, m / 3: m / 4:1215.5 m / 5:

[0128] compound 51 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVQLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4865.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.86 min, m / 3: m / 4:1217.2 m / 5:

[0129] compound 52 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17I,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4852.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.16 min, m / 3:1619.2 m / 4: m / 5:

[0130] compound 53 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17V,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEEVQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4838.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.20 min, m / 3:1613.2 m / 4:1210.0 m / 5:

[0131] compound 54 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEAQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4782.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.71 min, m / 3:1594.9 m / 4: m / 5:

[0132] compound 55 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,14E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASEEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4842.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.23min, m / 3:1614.8 m / 4: m / 5:

[0133] compound 56 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,14A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATAEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4798.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.04min, m / 3:1600.0 m / 4: m / 5:

[0134] compound 57 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,17A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEEAQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4724.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.20min, m / 3: m / 4:1182.0 m / 5:

[0135] compound 58 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17V,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEVQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.62 min, m / 3: m / 4:1203.4 m / 5:

[0136] compound 59 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,23Q,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVQLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4793.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.88 min, m / 3:1598.7 m / 4: m / 5:

[0137] compound 60 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22V,28Y,29Q,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHYYQWLTRQRY-NH2 Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.59min, m / 3:1609.4 m / 4: m / 5:

[0138] compound 61 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,10A,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPADASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4720.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.70min, m / 3: m / 4:1181.5 m / 5:

[0139] compound 62 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9P,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PPEDASPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4762.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.43min, m / 3:1588.6 m / 4: m / 5:

[0140] compound 63 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2

[0141] [ka] Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.35min, m / 3:1585.2 m / 4: m / 5:

[0142] compound 64 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDATPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4776.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.50min, m / 3: m / 4:1194.9 m / 5:

[0143] compound 65 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17I,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.18 min, m / 3: m / 4:1187.8 m / 5:

[0144] compound 66 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4838.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.60min, m / 3:1613.2 m / 4: m / 5:

[0145] compound 67 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEETQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4782.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.86 min, m / 3:1595.1 m / 4: m / 5:

[0146] compound 68 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22V,28Y,29Q,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVSLRHYYQWLTRQRY-NH2 Molecular weight (calculated): 4866.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.02 min, m / 3: m / 4:1217.4 m / 5:

[0147] compound 69 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,10A,17T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPADASPEETQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4708.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.50min, m / 3: m / 4:1178.1 m / 5:

[0148] compound 70 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4764.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.55 min, m / 3: m / 4:1192.4 m / 5:

[0149] compound 71 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.10min, m / 3: m / 4:1196.0 m / 5:

[0150] compound 72 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.71 min, m / 3:1598.4 m / 4: m / 5:

[0151] compound 73 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAASPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.24min, m / 3:1584.1 m / 4: m / 5:

[0152] compound 74 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.70min, m / 3: m / 4:1203.1 m / 5:

[0153] compound 75 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13P,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAPPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4820.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.30min, m / 3: m / 4:1207.1 m / 5:

[0154] compound 76 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P01 LCMS:U046_001, Rt:11.60min, m / 3:1609.0 m / 4: m / 5:

[0155] compound 77 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,28Q,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHYQNWLTRQRY-NH2 Molecular weight (calculated): 4717.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.51 min, m / 3:1572.9 m / 4:1180.4 m / 5:

[0156] compound 78 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,28Y,29Q,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHYYQWLTRQRY-NH2 Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.00min, m / 3:1589.9 m / 4: m / 5:

[0157] compound 79 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.11 min, m / 3: m / 4:1203.5 m / 5:

[0158] compound 80 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,14E,15A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASEAELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4784.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.52 min, m / 3:1594.9 m / 4: m / 5:

[0159] compound 81 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13Q,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAQPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4851.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.87 min, m / 3:1618.2 m / 4:1214.5 m / 5:

[0160] compound 82 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9P,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PPEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4720.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.36 min, m / 3:1574.2 m / 4: m / 5:

[0161] compound 83 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,14S,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATSEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4814.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.69 min, m / 3:1605.0 m / 4:1204.4 m / 5:

[0162] compound 84 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVALRHYYNWLTRQRY-NH2

[0163] [ka] Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.60min, m / 3: m / 4:1202.9 m / 5:

[0164] compound 85 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEETQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4740.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.15 min, m / 3: m / 4:1186.2 m / 5:

[0165] compound 86 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYASLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4796.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.67 min, m / 3: m / 4:1200.1 m / 5:

[0166] compound 87 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23P,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVPLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4834.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.25min, m / 3: m / 4:1209.3 m / 5:

[0167] compound 88 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,20Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRQYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4789.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.60min, m / 3:1596.6 m / 4: m / 5:

[0168] compound 89 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9P,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PPEDASPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4704.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.20min, m / 3:1568.4 m / 4: m / 5:

[0169] compound 90 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVVLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4836.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.76 min, m / 3: m / 4:1209.9 m / 5:

[0170] compound 91 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22T,28Y,29H,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYTSLRHYYHWLTRQRY-NH2 Molecular weight (calculated): 4877.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.22min, m / 3:1628.8 m / 4: m / 5:

[0171] compound 92 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PGEDASPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.75 min, m / 3:1585.3 m / 4:1188.4 m / 5:

[0172] compound 93 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17I,18Q,22V,23Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYVQLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4851.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.64 min, m / 3: m / 4:1213.4 m / 5:

[0173] compound 94 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEADASPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4736.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.07min, m / 3:1578.9 m / 4: m / 5:

[0174] compound 95 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19A,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQAYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4739.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.31min, m / 3:1579.5 m / 4: m / 5:

[0175] compound 96 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11S,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEESATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4796.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.90min, m / 3:1599.4 m / 4: m / 5:

[0176] compound 97 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22L,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYLSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4838.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.88 min, m / 3:1613.3 m / 4: m / 5:

[0177] compound 98 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4816.1 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.35min, m / 3:1606.6 m / 4: m / 5:

[0178] compound 99 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVALRHYYNWLTRQRY-NH2

[0179] [ka] Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.90min, m / 3: m / 4:1188.5 m / 5:

[0180] compound 100 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4764.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.10min, m / 3: m / 4:1192.2 m / 5:

[0181] Compound 101 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:12.28 min, m / 3: m / 4:1188.8 m / 5:

[0182] Compound 102 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,14L,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATLEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4840.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.96 min, m / 3:1613.9 m / 4:1210.9 m / 5:

[0183] compound 103 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,14A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASAEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4768.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.95 min, m / 3:1590.9 m / 4:1193.5 m / 5:

[0184] Compound 104 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEEAQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4882.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.00min, m / 3: m / 4:1221.8 m / 5:

[0185] compound 105 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,14Q,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATQEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4855.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.63 min, m / 3:1618.4 m / 4:1215.2 m / 5:

[0186] compound 106 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4736.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.50min, m / 3: m / 4:1185.0 m / 5:

[0187] Compound 107 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEETQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4840.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.30min, m / 3:1614.3 m / 4: m / 5:

[0188] compound 108 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,14E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASEEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4784.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.71 min, m / 3:1595.5 m / 4:1196.7 m / 5:

[0189] Compound 109 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12L,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDLTPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4866.6 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.14 min, m / 3:1623.2 m / 4:1216.9 m / 5:

[0190] compound 110 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4866.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.31 min, m / 3:1622.9 m / 4: m / 5:

[0191] Compound 111 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,11A,13E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEAAAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4692.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.12 min, m / 3:1564.1 m / 4:1173.3 m / 5:

[0192] compound 112 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4852.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.97min, m / 3: m / 4:1214.4 m / 5:

[0193] compound 113 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22V,28Q,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVSLRHYQNWLTRQRY-NH2 Molecular weight (calculated): 4789.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.23min, m / 3:1596.7 m / 4: m / 5:

[0194] compound 114 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVSLRHYYNWLTRQRY-NH2 [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.70min, m / 3: m / 4:1192.4 m / 5:

[0195] compound 115 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,21Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYQVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4789.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.17min, m / 3:1597.3 m / 4: m / 5:

[0196] compound 116 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,11A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEAAAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4676.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.62 min, m / 3:1559.2 m / 4: m / 5:

[0197] Compound 117 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEAQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.53min, m / 3:1584.9 m / 4: m / 5:

[0198] compound 118 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,13E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDAEPEEIQRYYVSLRHYYNWLTRQRY-NH2

[0199] [ka] Molecular weight (calculated): 4820.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.86 min, m / 3:1607.4 m / 4: m / 5:

[0200] Compound 119 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17S,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEESQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4798.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.92min, m / 3:1600.3 m / 4: m / 5:

[0201] compound 120 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4706.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.28 min, m / 3: m / 4:1177.1 m / 5:

[0202] compound 121 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,18Q,22V,23Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELQRYYVQLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4793.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.78 min, m / 3: m / 4:1199.3 m / 5:

[0203] compound 122 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAASPEELQRYYVSLRHYYNWLTRQRY-NH2

[0204] [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.40min, m / 3:1589.2 m / 4: m / 5:

[0205] compound 123 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13A,18Q,19K,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAAPEELQKYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.65 min, m / 3: m / 4:1192.1 m / 5:

[0206] compound 124 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11A,13E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEAAAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.74 min, m / 3:1583.7 m / 4: m / 5:

[0207] compound 125 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4852.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.93min, m / 3:1618.3 m / 4: m / 5:

[0208] compound 126 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4852.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.00min, m / 3:1617.0 m / 4: m / 5:

[0209] compound 127 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11A,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEAAAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.99min, m / 3: m / 4:1184.2 m / 5:

[0210] compound 128 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4780.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.70min, m / 3:1594.6 m / 4: m / 5:

[0211] compound 129 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,14A,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASAEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4784.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.37min, m / 3: m / 4:1197.0 m / 5:

[0212] compound 130 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19L,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQLYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4781.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.67min, m / 3:1595.1 m / 4: m / 5:

[0213] compound 131 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.83min, m / 3: m / 4:1195.0 m / 5:

[0214] compound 132 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.74min, m / 3:1589.6 m / 4: m / 5:

[0215] compound 133 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.12min, m / 3:1598.3 m / 4: m / 5:

[0216] compound 134 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17Q,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEQQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4839.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.04min, m / 3:1613.8 m / 4: m / 5:

[0217] compound 135 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEAAAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.45min, m / 3: m / 4:1184.2 m / 5:

[0218] compound 136 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELQRYYVALRHYYNWLTRQRY-NH2

[0219] [ka] Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.80min, m / 3:1584.4 m / 4: m / 5:

[0220] compound 137 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,28Y,30W,31L,32L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLLRQRY-NH2 Molecular weight (calculated): 4836.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.13min, m / 3:1558.4 m / 4: m / 5:

[0221] compound 138 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,19E,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQEYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4825.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.90 min, m / 3:1609.1 m / 4:1206.7 m / 5:

[0222] compound 139 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11E,15A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEEASPAELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.01 min, m / 3:1589.4 m / 4:1191.8 m / 5:

[0223] compound 140 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.21 min, m / 3:1585.1 m / 4: m / 5:

[0224] compound 141 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19S,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQSYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4755.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.40min, m / 3:1586.6 m / 4: m / 5:

[0225] compound 142 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13L,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDALPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4836.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:12.05 min, m / 3:1613.6 m / 4:1210.2 m / 5:

[0226] compound 143 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12S,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDSTPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4840.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.81 min, m / 3:1614.3 m / 4: m / 5:

[0227] compound 144 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12Q,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDQTPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4881.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.95 min, m / 3:1628.4 m / 4:1221.3 m / 5:

[0228] compound 145 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.37min, m / 3:1586.0 m / 4: m / 5:

[0229] compound 146 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11E,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEEATPEELQRYYVSLRHYYNWLTRQRY-NH2

[0230] [ka] Molecular weight (calculated): 4838.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.57 min, m / 3:1614.2 m / 4: m / 5:

[0231] compound 147 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.02min, m / 3:1603.9 m / 4: m / 5:

[0232] compound 148 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,23T,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVTLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4838.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.80min, m / 3: m / 4:1210.5 m / 5:

[0233] compound 149 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17S,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEESQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4726.3 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.28 min, m / 3: m / 4:1182.3 m / 5:

[0234] compound 150 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAASPEEIQRYYVSLRHYYNWLTRQRY-NH2

[0235] [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.30min, m / 3:1590.6 m / 4: m / 5:

[0236] Compound 151 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,12S,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDSSPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.05min, m / 3:1603.5 m / 4: m / 5:

[0237] compound 152 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEETQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4812.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.96 min, m / 3: m / 4:1204.0 m / 5:

[0238] compound 153 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11L,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEELATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4822.6 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.90min, m / 3: m / 4:1206.5 m / 5:

[0239] compound 154 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4764.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.68 min, m / 3:1588.4 m / 4: m / 5:

[0240] compound 155 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,28Y,30W,31L,32S]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLSRQRY-NH2 Molecular weight (calculated): 4810.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.33min, m / 3:1604.2 m / 4: m / 5:

[0241] compound 156 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEAAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4792.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.99 min, m / 3:1598.2 m / 4:1199.1 m / 5:

[0242] compound 157 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAASPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4692.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.45min, m / 3:1564.3 m / 4: m / 5:

[0243] compound 158 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,11A,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEAASPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4718.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.11 min, m / 3:1574.2 m / 4: m / 5:

[0244] Compound 159 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13E,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.63 min, m / 3: m / 4:1203.2 m / 5:

[0245] compound 160 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.49min, m / 3: m / 4:1188.2 m / 5:

[0246] compound 161 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13E,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAAEPEELQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.00min, m / 3: m / 4:1184.0 m / 5:

[0247] compound 162 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEEQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4840.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.20min, m / 3: m / 4:1211.0 m / 5:

[0248] compound 163 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELQRYYVALRHYYNWLTRQRY-NH2

[0249] [ka] Molecular weight (calculated): 4736.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.30min, m / 3: m / 4:1184.5 m / 5:

[0250] compound 164 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22Q,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYQSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4853.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.44min, m / 3:1618.6 m / 4: m / 5:

[0251] compound 165 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9P,13E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PPEDAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4762.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.11 min, m / 3:1587.7 m / 4: m / 5:

[0252] compound 166 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.76 min, m / 3: m / 4:1199.2 m / 5:

[0253] compound 167 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEAAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.49min, m / 3: m / 4:1185.0 m / 5:

[0254] compound 168 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22S,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYSSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4812.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.83min, m / 3:1605.7 m / 4: m / 5:

[0255] compound 169 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,18Q,19A,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQAYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4767.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:13.90 min, m / 3:1589.0 m / 4:1192.1 m / 5:

[0256] compound 170 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13A,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAAPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.60min, m / 3: m / 4:1199.0 m / 5:

[0257] Compound 171 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,18Q,22V,23E,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELQRYYVELRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.57 min, m / 3:1599.2 m / 4: m / 5:

[0258] compound 172 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9P,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PPEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.95min, m / 3:1593.5 m / 4: m / 5:

[0259] compound 173 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.50min, m / 3:1609.0 m / 4: m / 5:

[0260] compound 174 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,10A,16K,18Q,22V,28Y,29H,30K,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PGADASPEKLQRYYVSLRHYYHKLTRQRY-NH2 Molecular weight (calculated): 4644.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:7.90min, m / 3:1548.8 m / 4: m / 5:

[0261] compound 175 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13E,18Q,22I,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYIALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4792.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.86 min, m / 3: m / 4:1198.8 m / 5:

[0262] compound 176 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVSLRHYYNWLTRQRY-NH2

[0263] [ka] Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.84min, m / 3:1610.6 m / 4: m / 5:

[0264] compound 177 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,19Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQQYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4796.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.00min, m / 3: m / 4:1200.0 m / 5:

[0265] compound 178 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11A,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEAAATPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4706.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.21 min, m / 3: m / 4:1177.0 m / 5:

[0266] Compound 179 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,17T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEETQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4724.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.50min, m / 3: m / 4:1181.4 m / 5:

[0267] compound 180 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,28Y,30W,31L,33K]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLTKQRY-NH2 Molecular weight (calculated): 4796.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.80min, m / 3:1600.8 m / 4: m / 5:

[0268] compound 181 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEADAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4720.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.23 min, m / 3:1574.1 m / 4:1180.8 m / 5:

[0269] compound 182 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17A,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEAQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4694.3 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.70min, m / 3:1565.3 m / 4: m / 5:

[0270] compound 183 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,8A,9E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)AEEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4784.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.60min, m / 3:1595.9 m / 4: m / 5:

[0271] compound 184 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,13T,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADATPEEIQRYYVALRHYYNWLTRQRY-NH2

[0272] [ka] Molecular weight (calculated): 4750.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.00min, m / 3: m / 4:1188.5 m / 5:

[0273] compound 185 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,14E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASEEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4784.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.80min, m / 3:1595.2 m / 4: m / 5:

[0274] compound 186 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13E,17A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEEAQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4810.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:13.20min, m / 3: m / 4:1203.8 m / 5:

[0275] compound 187 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17P,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEPQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4808.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:9.38 min, m / 3:1603.3 m / 4: m / 5:

[0276] compound 188 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,18Q,22V,28Y,30W,31L,32Q]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELQRYYVSLRHYYNWLQRQRY-NH2 Molecular weight (calculated): 4851.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:11.13min, m / 3:1618.0 m / 4: m / 5:

[0277] compound 189 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17T,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEETQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4724.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:11.50min, m / 3: m / 4:1182.1 m / 5:

[0278] compound 190 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13T,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEELQRYYISLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4780.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.28 min, m / 3:1594.5 m / 4: m / 5:

[0279] Compound 191 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,13T,17I,18Q,22E,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYESLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4854.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:9.77min, m / 3:1619.0 m / 4: m / 5:

[0280] compound 192 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,11P,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEAPASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4734.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.39min, m / 3: m / 4:1184.5 m / 5:

[0281] compound 193 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,11E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEEASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4824.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:12.20min, m / 3:1609.1 m / 4: m / 5:

[0282] compound 194 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,13E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4778.5 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.80min, m / 3: m / 4:1195.1 m / 5:

[0283] Compound 195 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,17I,18Q,22I,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYISLRHYYNWLTRQRY-NH2

[0284] [ka] Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.02 min, m / 3: m / 4:1192.4 m / 5:

[0285] compound 196 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,10A,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4752.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.35min, m / 3:1584.8 m / 4: m / 5:

[0286] Compound 197 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,7K,9E,17I,18Q,22V,23A,28Y,30W,31L]-hPYY(4-36) iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYVALRHYYNWLTRQRY-NH2

[0287] [ka] Molecular weight (calculated): 4794.5 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.19min, m / 3: m / 4:1199.4 m / 5:

[0288] Compound 198 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,10A,13E,17I,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEADAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4736.4 Da Methods of synthesis and purification: S01, P02 LCMS:010_CA07, Rt:10.70min, m / 3: m / 4:1184.9 m / 5:

[0289] Compound 199 N{alpha-4}-(3-methylbutanoyl)-N{epsilon-7}-(6-[(4S)-4-carboxy-4-(17-carboxyheptadecanamido)butanamido]hexanoyl)-[4A,6A,7K,9E,11E,18Q,22V,28Y,30W,31L]-hPYY(4-36) iVal-APAK(C18DA-gGlu-Ahx)PEEEASPEELQRYYVSLRHYYNWLTRQRY-NH2 Molecular weight (calculated): 4766.4 Da Methods of synthesis and purification: S01, P01 LCMS:010_CA07, Rt:10.40min, m / 3: m / 4:1192.0 m / 5:

[0290] The following compound disclosed as Example 32 in International Publication No. WO2016 / 198682 was synthesized as a reference compound. Reference compound 1 iVal-RPEK(C18DA-gGlu-Ahx)PGEDASPEELQRYYISLRHYYNWLTRQRY-NH2 (SEQ ID NO: 204) Further compounds were synthesised as reference compounds. Reference compound 2 iVal-RPEK(C18DA-gGlu-Ahx)PGEDASPEELQRYYISLAHYYNWLTRQRY-NH2 (SEQ ID NO: 205) Reference compound 3 iVal-RPEK(C18DA-gGlu-Ahx)PGEDASPEELQRYYISLRHYYNWLTAQRY-NH2 (SEQ ID NO: 206) Reference compound 4 iVal-RPEK(C18DA-gGlu-Ahx)PGEDASPEELQRYYISLRHYYNWLTRQAY-NH2 (SEQ ID NO: 207)

[0291] The structure of reference compound 1 is identical to compound 92, except for the alanine at position 4. This R4A mutation results in a compound that is much more soluble at pH 6.2 (0.0 mg / ml for reference compound 1 vs. 9.2 mg / ml for compound 92). At the same time, high binding affinity and receptor activity are maintained in compound 92 (see Table 2). Other arginine to alanine mutations at different positions (R25A in reference compound 2, R33A in reference compound 3, R35A in reference compound 4) negatively affect the binding affinity and receptor activity of the resulting compounds.

[0292] [Table 3] EXAMPLES

[0293] The following examples illustrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those skilled in the art, unless otherwise specified in detail.

[0294] Example 1 Radioligand binding competition assay (RLB) Filtration RLB assays were performed in 96-well plates in a final volume of 100 μl per well. Lyophilized test peptides were dissolved in 100% dimethyl sulfoxide (DMSO) to a stock solution of 1 mM and serially diluted in assay buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, pH 7.4) containing 0.2% ovalbumin. 10 μl / well of test peptide solution was added to the plate to give final concentrations ranging from 1 μM to 3 pM. This was followed by 10 μl / well of human IgG in assay buffer containing 0.2% ovalbumin. 12510 μl of I-PYY(1-36) (Perkin Elmer) was added to the wells to give a final concentration of 0.02 nM. Then, 80 μL of membrane (HTS066M, ChemiSCREEN™ Human Neuropeptide Y2 Receptor Membrane Preparation, CHEMICON) was added to each well to give a final protein concentration of 0.5 μg / well. The plate was sealed and incubated for 2 hours at room temperature on a plate shaker set at 400 rpm. The incubation was stopped by vacuum filtration onto GF / C filters presoaked in 0.5% polyethyleneimine (PEI) using a 96-well FilterMate™ harvester (Perkin Elmer), followed by 4 washes with 300 μl / well of ice-cold wash buffer (50 mM HEPES, 500 mM NaCl, pH 7.4). The filter plate was then dried at room temperature for 60 minutes and the bottom of the plate was sealed with backing tape UniFilter-96. Finally, 50 μl / well of scintillation counter cocktail (Microscint20, Packard) was added and radioactivity was counted in a Packard TopCount NXT scintillation counter. 50 The IC values ​​(half-maximal inhibitory concentrations of agonists) were calculated by nonlinear regression analysis of sigmoidal dose-response curves. The binding affinity Ki values ​​were obtained by the Cheng-Prusoff equation (Ki=IC 50 / (1+[L] / Kd)), where Kd is the receptor-specific dissociation constant previously measured (=0.07 nM for NPY2R) and [L] is 125 I-PYY(1-36) radioligand concentration.

[0295] The RLB results are summarized in Table 3 below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] In general, data obtained with the RLB assay are predictive of acute food intake inhibition in mice (Experiment 6).

[0296] Example 2 HTRF cAMP Gi assay Homogeneous time-resolved fluorescence (HTRF) technology optimized for Gi-coupled receptors is described in detail in the Cisbio cAMP Gi kit manual. Briefly, intracellular cAMP production results in competition between unlabeled cAMP and exogenously added d2-cAMP for anti-cAMP antibodies conjugated to cryptate. CHO-K1 cells stably expressing human NPY1, NPY2, NPY4, and NPY5 receptors were used with cells restored from frozen stocks immediately prior to assay run. 2000 cells per well were applied for all four NPY receptor subtype assays. A 384-well format was used, with 5 μl of cells, 2.5 μl of peptide agonist, 2.5 μl of forskolin, and 5 μl of each fluorophore applied in a total volume of 20 μl. Cells were incubated with agonist peptides (11-point concentration-response curves) and forskolin (~90% activity level, 3-11 μM forskolin) for 40 min at 37°C using DPBS containing 0.5 mM IBMX as stimulation buffer. HTRF® detection reagent was added and signals at 620 and 665 nm (raw counts: 665 / 620 ratio) were detected after 1 h incubation at room temperature with shaking (2400 rpm). Compound concentration-response evaluation was performed using 11 concentrations of agonist peptides (covering 3 decades). EC 50 Values ​​were calculated by nonlinear regression using a variable slope sigmoidal concentration response.

[0297] In vitro activity results (EC 50 The following table summarizes the results of the experiments (expressed as values): [Table 5]

[0298] Example 3 Determining stability Peptides (as TFA salts) were weighed into filter units (Mini-UniPrep Syringeless Filter 0.45 μm, Whatman) and 0.1 M dibasic sodium phosphate buffer, pH 6.4 or 7.0, was added to achieve a final concentration of 10 mg / ml. The peptides were dissolved by shaking the filter units horizontally at 600 rpm for 2 hours at room temperature. Samples were filtered to remove any insoluble particles and diluted to 1 mg / ml in 50% acetonitrile. Controls were prepared by weighing the corresponding peptide and dissolving it in 50% acetonitrile to a final concentration of 1 mg / ml. Both controls and samples were analyzed by reversed-phase chromatography. The area under the peaks of the samples was compared to the control and the solubility was calculated based on the ratio.

[0299] For each sample, the pH was measured and recorded. Typically, the pH of the buffer was reduced by 0.2-0.3 pH units due to the TFA content of the peptide. UPLC method: System: UltiMate 3000 UPLC, ThermoFisher Mobile phase A: 5% acetonitrile, 95% water, 0.03% trifluoroacetic acid Mobile phase B: 95% acetonitrile, 5% water, 0.03% trifluoroacetic acid Flow rate: 1ml / min Gradient: 0-100% mobile phase B (2 min) Column: Kinetix, 5 μm C8, 100 Å, 50 × 2.1 mm Column temperature: 50℃

[0300] The results of the solubility determination are summarized in Table 5 below. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0301] Example 4 DLS research Aggregation combined with particle growth in peptide solutions was detected by dynamic light scattering (DLS). Test peptides (5 mg / ml) were dissolved in 50 mM phosphate buffer with EDTA (0.05 mg / ml), which was adjusted to a final pH of 7.2. The solutions were filtered through a 0.2 μm filter and shaken on a laboratory shaker at approximately 150 rpm at room temperature for 5-7 days. Samples were analyzed with a particle size analyzer (DLS, Horiba Nano Particle Analyzer SZ-100) on day 0 and at the end of the study. The formation of aggregates was detected by the increase in particle size over time and was assessed as OK, indicating no increase in particle size, and NOK, indicating an increase in particle size.

[0302] The results from the DLS studies are summarized in Table 6. [Table 7]

[0303] Example 5 Mouse PK Pharmacokinetic parameters of the test compounds were determined following intravenous administration to NMRI mice. Male NMRI mice weighing approximately 30-40 g were obtained from either Charles River (Germany) or Janvier (France). Mice were housed in standard cages with a light-dark cycle of 12 h dark and 12 h light. Standardized diet and water were provided ad libitum to the animals throughout the experimental period. Each peptide was dissolved in 50 mM phosphate buffer (pH 7.0) containing 5% mannitol. An intravenous dose of 30 nmol / kg was given via the tail vein.

[0304] Serial blood samples were collected from the saphenous vein at different time points up to 48 hours post-dose into tubes containing EDTA as anticoagulant. After centrifugation for approximately 5 minutes, plasma samples were transferred to a 96-well PCR plate, immediately frozen, and stored at approximately -20°C until analyzed for plasma concentrations by liquid chromatography-mass spectrometry (LC-MS / MS). Individual plasma concentration-time profiles were analyzed by a non-compartmental approach to determine the resulting pharmacokinetic parameters.

[0305] [Table 8] The measured mouse MRTs of the PYY analogues according to the invention are comparable to that of reference compound 1 and show a significantly longer half-life compared to that of hPYY(3-36).

[0306] Example 6 Effects on acute food intake in normal NMRI mice Five-week-old male NMRI mice were obtained from Charles River (Charles River, Research Models & Services Germany GmbH) or JanVier (JanVier Labs, France). Animals were housed in groups of 4 mice per cage under a 12 / 12-h light-dark cycle with lights off at 3 PM. Room temperature was controlled at 21° C.±1° C. with 60%±20% humidity. Animals were fed regular rodent chow (KLIBA Nafag 3430 or Altromin 1324, Brogaarden, Denmark) and tap water ad libitum.

[0307] Animals were transferred to a real-time food intake monitoring system HM-2 system (MBRose, Denmark) 5-7 days before the start of the study to acclimate them to the experimental conditions. Since the animals were uniquely identified by microchips, each individual animal was identified by its microchip when entering and exiting the food channel. Randomization of mice (n=7-8) in each study group was based on body weight measured the day before the start of the study. A vehicle-treated (50 mM phosphate buffer, pH 7, containing 5% mannitol) group was included in each experiment. Animals were fasted 6 hours before the start of the night phase. One hour before the dark phase, animals were dosed subcutaneously with the test peptide (5 nmol / kg) once. Food intake was reported every hour for a 24-hour period. Food intake of the treatment groups was normalized to the mean food intake of the group that received vehicle (in %) (Table 7). Statistical significance was assessed using one-way ANOVA with Tukey's multiple comparison test. P<0.05 was considered statistically significant.

[0308] [Table 9]

[0309] Example 7 Activity after incubation in solutions of different pH values Peptides (as TFA salts) were weighed into filter units (Mini-UniPrep Syringeless Filter 0.45 μm, Whatman) and 0.1 M dibasic sodium phosphate buffer, pH 6.4 or 7.4, respectively, or 0.2 M TRIS buffer, pH 8.3, was added to achieve a final concentration of 10 mg / ml. The peptides were (partially) dissolved by horizontally shaking the filter units at approximately 400 rpm for 2 hours at room temperature. The samples were filtered to remove any insoluble particles. The filtrates were then subjected to the binding assay described in Example 1. The apparent binding affinities (Ki) reported in Table 8 are calculated based on an assumed concentration of 10 mg / ml. The compounds of the invention are active in the binding assay after incubation in solutions of different pH values, including pH 6. This demonstrates the fundamental feasibility of liquid formulations of the compounds according to the invention at about pH 6 (pH range of about 6 to about 8).

[0310] In contrast, after incubation at about pH 6, solutions of reference compound 1 (after filtration) show a weak response in the binding assay (apparent significant (>45-fold) loss of affinity due to the low solubility of reference compound 1 in buffered media at pH 6). Thus, the inherently low solubility of reference compound 1 at about pH 6 limits the formulation scope of liquid formulations of reference compound 1 in the physiological pH range of 6-8.

[0311] [Table 10]

Claims

1. 1. A PYY analog having the formula: R 1 -Z-R 2 or a salt thereof, wherein R 1 is hydrogen, -C(O)C 1-6 Alkyl, -C(O)C 6 H 6 , -C(O)C 3-6 Cycloalkyl, —C(O)C 1-6 Alkyl-C 3-6 Cycloalkyl, C 1-6 Alkyl, or C 1-6 Alkyl-C 3-6 is cycloalkyl, R 2 is OH or NHR 3 Wherein R 3 is hydrogen or C 1-3 is alkyl, Z is an amino acid sequence of formula IIb: Ala-Pro-X6-Lys-X8-X9-X10-X11-Ala-X13-X14-Glu-Glu-X17-Gln-X19-Tyr-T yr-X22-X23-Leu-Arg-His-Tyr-Tyr-X29-Trp-Leu-Thr-Arg-Gln-Arg-Tyr (IIb) A peptide consisting of the formula: X6 is selected from the group consisting of Ala and Glu; X8 is selected from the group consisting of Ala and Pro; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X14 is selected from the group consisting of Ala, Glu, and Pro; X17 is selected from the group consisting of Ala, Ile, Leu, Ser, and Thr; X19 is selected from the group consisting of Arg and Gln; X22 is selected from the group consisting of He, Thr, and Val; X23 is selected from the group consisting of Ala, Glu, Gln, and Ser; X29 is selected from the group consisting of Asn and Gln, and up to three residues of X6 to X23 are Ala; at least four of residues X6, X9, X10, X13, X15, X16, and X23 are GIu; a half-life extending group is attached to the epsilon amino group of the lysine at position 7; the half-life extending group comprises a lipophilic substituent X and a linker U, the linker U being attached to an amino acid side chain, and the lipophilic substituent X being attached to the linker U; the linker U consists of one, two or three submoieties (U1, U2, U3) independently selected from the group consisting of Gly, Glu, γ-Glu, ε-Lys, Ser, Ahx and OEG, at least one submoiety being Ahx (6-aminohexanoic acid); said lipophilic substituent X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, and 19-carboxy-nonadecanoyl; PYY analogue.

2. Z is an amino acid sequence of formula IIIb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-Ala-X13-X14-Glu-Glu-X17-Gln-X19-Tyr-T yr-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr (IIIb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X14 is selected from the group consisting of Ala, Glu, and Pro; X17 is selected from the group consisting of Ile, Leu, and Thr; X19 is selected from the group consisting of Arg and Gln; X22 is selected from the group consisting of He, and Val; X23 is selected from the group consisting of Ala, Glu, and Ser; The PYY analog of claim 1.

3. Z is an amino acid sequence of formula IVb: Ala-Pro-X6-Lys-Pro-X9-X10-X11-Ala-X13-Pro-Glu-Glu-X17-Gln-Arg-Tyr-T yr-X22-X23-Leu-Arg-His-Tyr-Tyr-Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr (IVb) where: X6 is selected from the group consisting of Ala and Glu; X9 is selected from the group consisting of Glu and Pro; X10 is selected from the group consisting of Ala and Glu; X11 is selected from the group consisting of Ala, Asp, and Glu; X13 is selected from the group consisting of Glu, Ser, and Thr; X17 is selected from the group consisting of He, and Leu; X22 is selected from the group consisting of He, and Val; X23 is selected from the group consisting of Ala and Ser; The PYY analog of claim 1.

4. 4. The PYY analog of any one of claims 1 to 3, wherein the PYY analog has 7 or more and 15 or less amino acid modifications compared to hPYY(3-36).

5. Z is selected from the group consisting of SEQ ID NOs: 5, 6, 8, 10, 11, 15, 17, 18, 19, 22, 23, 25, 27, 29, 30, 31, 32, 37, 38, 39, 40, 41, 44, 45, 51, 52, 54, 55, 56, 58, 59, 60, 61, 63, 64, 66, 67, 68, 69, 70, 71, 72, 74, 75, 76, 77, 78, 80, 82, 83, 88, 89, 97, 98, 102, 103, 104, 105, 107, 108, 110, 111, 112, 114, 116, 118, 121, 122, 12 2. The PYY analog of claim 1, which is an amino acid sequence selected from:

6. R 1 is -C(O)CH 2 CH (CH 3 ) 2 , -C(O)CH 2 -cyclobutyl, and -C(O)CH 2 The PYY analogue of any one of claims 1 to 5, which is selected from the group consisting of: -cyclopropyl.

7. The PYY analog is selected from the group consisting of the compounds: Compound 1 iVal-APEK (C18DA-gGlu-Ahx) PEADAEPEELQRYYIALRHYYNWLTRQRY-NH2 Compound 2 iVal-APEK (C18DA-gGlu-Ahx) PEEDASPEELQRYYIALRHYYNWLTRQRY-NH2 Compound 4 iVal-APEK (C18DA-gGlu-Ahx) PEEAAEPEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 6 iVal-APEK (C18DA-gGlu-Ahx) PEADAEPEELQRYYVALRHYYNWLTRQRY-NH2 Compound 7 iVal-APEK (C18DA-gGlu-Ahx) PEADATPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 11 iVal-APEK (C18DA-gGlu-Ahx) PEADASPEEIQRYYISLRHYYNWLTRQRY-NH2 Compound 13 iVal-APEK (C18DA-gGlu-Ahx) PEADASPEETQRYYVSLRHYYNWLTRQRY-NH2 Compound 14 iVal-APEK(C18DA-gGlu-Ahx)PPEDASPEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 15 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEIQQYYSLRHYYNWLTRQRY-NH2 Compound 18 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELQRYYVALRHYYNWLTRQRY-NH2 Compound 19 iVal-APEK(C18DA-gGlu-Ahx)PEEDATEEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 21 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYVALRHYYNWLTRQRY-NH2 Compound 23 iVal-APEK(C18DA-gGlu-Ahx)PEEEEASPEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 25 iVal-APEK(C18DA-gGlu-Ahx)PEADATPPEELQRYYISLRHYYNWLTRQRY-NH2 Compound 26 iVal-APAK(C18DA-gGlu-Ahx)PEEDATPPEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 27 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEESQRYYVSLRHYYNWLTRQRY-NH2 Compound 28 iVal-APEK(C18DA-gGlu-Ahx)PPEDATPPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 33 iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYISLRHYYNWLTRQRY-NH2 Compound 34 iVal-APEK(C18DA-gGlu-Ahx)PEEDASAEELQQYYVSLRHYYNWLTRQRY-NH2 Compound 35 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPPEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 36 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 37 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYTSLRHYYNWLTRQRY-NH2 Compound 40 iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEIQRYYIALRHYYNWLTRQRY-NH2 Compound 41 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEEPPEELQRYYTSLRHYYQWLTQRRY-NH2 Compound 47 iVal-APEK(C18DA-gGlu-Ahx)PPEDASPPEEIQRYYVALRHYYNWLTQRRY-NH2 Compound 48 iVal-APAK(C18DA-gGlu-Ahx)PEEAAATPPEELQRYYISLRHYYNWLTQRRY-NH2 Compound 50 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPPEEIQRYYVALRHYYNWLTQRRY-NH2 Compound 51 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPPEELQRYYVQLRHYYNWLTQRRY-NH2 Compound 52 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPPEEIQRYYVELRHYYNWLTQRRY-NH2 Compound 54 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPPEEAQRYYVSLRHYYNWLTQRRY-NH2 Compound 55 iVal-APEK(C18DA-gGlu-Ahx)PEEDASEEEEIQRYYVSLRHYYNWLTQRRY-NH2 Compound 56 iVal-APEK(C18DA-gGlu-Ahx)PEEDATAEEELQRYYVSLRHYYNWLTQRRY-NH2 Compound 57 iVal-APAK(C18DA-gGlu-Ahx)PEEDATPPEEAQRYYVSLRHYYNWLTQRRY-NH2 Compound 59 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPPEELQRYYVQLRHYYNWLTQRRY-NH2 Compound 60 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPPEELQRYYVSLRHYYQWLTQRRY-NH2 Compound 62 iVal-APAK(C18DA-gGlu-Ahx)PPEDASPPEELQRYYVELRHYYNWLTQRRY-NH2 Compound 63 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPPEEIQRYYVSLRHYYNWLTQRRY-NH2 Compound 64 iVal-APEK(C18DA-gGlu-Ahx)PPEDATPPEEIQRYYVALRHYYNWLTQRRY-NH2 Compound 65 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYYALRHYYNWLTRQRY-NH2 Compound 66 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEELQRYYYISLRHYYNWLTRQRY-NH2 Compound 67 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEEETQRYYYVALRHYYNWLTRQRY-NH2 Compound 68 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYYVSLRHYYQWLTRQRY-NH2 Compound 70 iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEEELQRYYYIALRHYYNWLTRQRY-NH2 Compound 71 iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYYVALRHYYNWLTRQRY-NH2 Compound 72 iVal-APEK(C18DA-gGlu-Ahx)PEADAEPPEELQRYYYVSLRHYYNWLTRQRY-NH2 Compound 73 iVal-APEK(C18DA-gGlu-Ahx)PEEAASPPEELQRYYYVALRHYYNWLTRQRY-NH2 Compound 74 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEELQRYYYVALRHYYNWLTRQRY-NH2 Compound 76 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPPEELQRYYYISLRHYYNWLTRQRY-NH2 Compound 78 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPPEELQRYYYVSLRHYYQWLTRQRY-NH2 Compound 79 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPPEELQRYYYVSLRHYYNWLTRQRY-NH2 Compound 84 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPPEEIQRYYYVALRHYYNWLTRQRY-NH2 Compound 85 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPPEETQRYYYVSLRHYYNWLTRQRY-NH2 Compound 93 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPPEEIQRYYYVQLRHYYNWLTRQRY-NH2 Compound 94 iVal - APAK(C18DA - gGlu - Ahx)PEADASPPEELQRYYVELRHYYNWLTRQRY - NH2 Compound 98 iVal - APEK(C18DA - gGlu - Ahx)PEADATPPEEIQRYYVSLRHYYNWLTRQRY - NH2 Compound 99 iVal - APAK(C18DA - gGlu - Ahx)PEEDATPPEEIQRYYVALRHYYNWLTRQRY - NH2 Compound 100 iVal - APEK(C18DA - gGlu - Ahx)PEADATPPEELQRYYIALRHYYNWLTRQRY - NH2 Compound 101 iVal - APAK(C18DA - gGlu - Ahx)PEEDATPPEELQRYYVALRHYYNWLTRQRY - NH2 Compound 103 iVal - APEK(C18DA - gGlu - Ahx)PEEDASAEEELQRYYVALRHYYNWLTRQRY - NH2 Compound 104 iVal - APEK(C18DA - gGlu - Ahx)PEEDAEPEEAQRYYVSLRHYYNWLTRQRY - NH2 Compound 106 iVal - APAK(C18DA - gGlu - Ahx)PEEDASPPEELQRYYVALRHYYNWLTRQRY - NH2 Compound 107 iVal - APEK(C18DA - gGlu - Ahx)PEEDAEPEETQRYYVSLRHYYNWLTRQRY - NH2 Compound 108 iVal - APEK(C18DA - gGlu - Ahx)PEADASEEEEELQRYYVSLRHYYNWLTRQRY - NH2 Compound 110 iVal - APEK(C18DA - gGlu - Ahx)PEEDATPPEELQRYYVELRHYYNWLTRQRY - NH2 Compound 112 iVal - APEK(C18DA - gGlu - Ahx)PEEDAEPEEIQRYYVSLRHYYNWLTRQRY - NH2 Compound 114 iVal - APAK(C18DA - gGlu - Ahx)PEEDATPPEEIQRYYVSLRHYYNWLTRQRY - NH2 Compound 117 iVal - APEK(C18DA - gGlu - Ahx)PEEDASPPEAQRYYVALRHYYNWLTRQRY - NH2 Compound 118 iVal - APEK(C18DA - gGlu - Ahx)PPEDAEPEEIQRYYVSLRHYYNWLTRQRY - NH2 Compound 119 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEESEQRYYVSLRHYYNWLTRQRY-NH2 Compound 120 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVALRHYYNWLTRQRY-NH2 Compound 121 iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELLQRYYVQLRHYYNWLTRQRY-NH2 Compound 122 iVal-APEK(C18DA-gGlu-Ahx)PEAEASPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 124 iVal-APEK(C18DA-gGlu-Ahx)PEAAAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 125 iVal-APEK(C18DA-gGlu-Ahx)PEEDASPEELLQRYYVELRHYYNWLTRQRY-NH2 Compound 126 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 128 iVal-APEK(C18DA-gGlu-Ahx)PEEAATPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 129 iVal-APEK(C18DA-gGlu-Ahx)PEEDASAEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 131 iVal-APEK(C18DA-gGlu-Ahx)PEADAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Compound 132 iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 133 iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 136 iVal-APEK(C18DA-gGlu-Ahx)PEADATPEELLQRYYVALRHYYNWLTRQRY-NH2 Compound 140 iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 145 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 146 iVal - APEK(C18DA - gGlu - Ahx)PEEEATPPEELQRYYYVSLRHYYNWLTRQRY - NH2 Compound 147 iVal - APEK(C18DA - gGlu - Ahx)PEEDASPPEEIQRYYYVSLRHYYNWLTRQRY - NH2 Compound 149 iVal - APAK(C18DA - gGlu - Ahx)PEEDASPPEESQRYYYVSLRHYYNWLTRQRY - NH2 Compound 150 iVal - APEK(C18DA - gGlu - Ahx)PEEAASPPEEIQRYYYVSLRHYYNWLTRQRY - NH2 Compound 152 iVal - APEK(C18DA - gGlu - Ahx)PEEDATPPEETQRYYYVSLRHYYNWLTRQRY - NH2 Compound 154 iVal - APEK(C18DA - gGlu - Ahx)PEEAATPPEEIQRYYYVALRHYYNWLTRQRY - NH2 Compound 156 iVal - APEK(C18DA - gGlu - Ahx)PEAAEPPEEIQRYYYVALRHYYNWLTRQRY - NH2 Compound 158 iVal - APEK(C18DA - gGlu - Ahx)PPEAASPPEEIQRYYYVALRHYYNWLTRQRY - NH2 Compound 159 iVal - APEK(C18DA - gGlu - Ahx)PEADAEPPEELQRYYYISLRHYYNWLTRQRY - NH2 Compound 160 iVal - APAK(C18DA - gGlu - Ahx)PEEDASPPEELQRYYYIALRHYYNWLTRQRY - NH2 Compound 163 iVal - APEK(C18DA - gGlu - Ahx)PEADASPPEELQRYYYVALRHYYNWLTRQRY - NH2 Compound 165 iVal - APAK(C18DA - gGlu - Ahx)PPEDAEPPPEELQRYYYVSLRHYYNWLTRQRY - NH2 Compound 166 iVal - APAK(C18DA - gGlu - Ahx)PEEDASPPEELQRYYYVELRHYYNWLTRQRY - NH2 Compound 171 iVal - APEK(C18DA - gGlu - Ahx)PEADASPPEELQRYYYVELRHYYNWLTRQRY - NH2 Compound 172 iVal - APEK(C18DA - gGlu - Ahx)PPEDASPPEEIQRYYYVSLRHYYNWLTRQRY - NH2 Compound 173 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 175 iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEELQRYYIALRHYYNWLTRQRY-NH2 Compound 176 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 177 iVal-APEK(C18DA-gGlu-Ahx)PEEDATPEELLQQYYVSLRHYYNWLTRQRY-NH2 Compound 179 iVal-APEK(C18DA-gGlu-Ahx)PEADASPEEQTQRYYVALRHYYNWLTRQRY-NH2 Compound 183 iVal-APEK(C18DA-gGlu-Ahx)AEEDASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 184 iVal-APEK(C18DA-gGlu-Ahx)PEADATPEEIQRYYVALRHYYNWLTRQRY-NH2 Compound 185 iVal-APAK(C18DA-gGlu-Ahx)PEEDASEEELQRYYVSLRHYYNWLTRQRY-NH2 Compound 186 iVal-APEK(C18DA-gGlu-Ahx)PEEDAEPEEAQRYYVSLRHYYNWLTRQRY-NH2 Compound 189 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEQTQRYYVALRHYYNWLTRQRY-NH2 Compound 190 iVal-APAK(C18DA-gGlu-Ahx)PEEDATPEELLQRYYISLRHYYNWLTRQRY-NH2 Compound 193 iVal-APEK(C18DA-gGlu-Ahx)PEEEASPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 194 iVal-APAK(C18DA-gGlu-Ahx)PEEDAEPEEIQRYYVALRHYYNWLTRQRY-NH2 Compound 195 iVal-APAK(C18DA-gGlu-Ahx)PEEDASPEEIQRYYISLRHYYNWLTRQRY-NH2 Compound 196 iVal-APEK(C18DA-gGlu-Ahx)PEADASPEELLQRYYVSLRHYYNWLTRQRY-NH2 Compound 197 iVal-APEK (C18DA-gGlu-Ahx) PEEDASPEEIQRYYVALRHYYNWLTRQRY-NH2 Compound 198 iVal-APAK(C18DA-gGlu-Ahx)PEADAEPEEIQRYYVSLRHYYNWLTRQRY-NH2 Compound 199 iVal-APAK(C18DA-gGlu-Ahx)PEEEASPEELQRYYVSLRHYYNWLTRQRY-NH2 (wherein iVal is 3-methylbutanoyl (—C(O)CH 2 CH (CH 3 ) 2 ) C18DA stands for 17-carboxyheptadecanoyl; gGlu represents L-γ-glutamyl connected through its amino group to C18DA and through its γ-carboxy group to Ahx; Ahx represents 6-amino-hexanoyl connected through its amino group to gGlu and through its carboxy group to the ε-amino group of lysine (K).

7. The PYY analogue of any one of claims 1 to 6, which is a compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

8. The PYY analogue of any one of claims 1 to 7, in the form of a pharma- ceutically acceptable salt.

9. 2. The PYY analog of claim 1, wherein the PYY analog is a compound selected from the group consisting of: Compound 7: Compound 26: Compound 40: Compound 63: Compound 84: Compound 114: Compound 136: Compound 146: Compound 163: Compound 176: and Compound 197:

10. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 7:

11. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 40:

12. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 84:

13. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 146:

14. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 163:

15. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 176:

16. 2. The PYY analog of claim 1, wherein the PYY analog is the following compound or a pharma- ceutically acceptable salt thereof: Compound 197:

17. The PYY analogue of any one of claims 1 to 16, having a binding affinity (Ki) to hNPY2R of less than 100 nM.

18. 18. The PYY analogue of any one of claims 1 to 17, wherein the solubility of the PYY analogue is greater than 1.0 mg / ml at pH 6.1±0.

2.

19. The PYY analog is the compound: Compound 35 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEELQRYYVSLRHYYNWLTRQRY-NH2, Compound 36 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVSLRHYYNWLTRQRY-NH2, Compound 48 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEELQRYYISLRHYYNWLTRQRY-NH2, Compound 120 iVal-APAK(C18DA-gGlu-Ahx)PEEAATPEEIQRYYVALRHYYNWLTRQRY-NH2, Compound 158 iVal-APEK (C18DA-gGlu-Ahx) PPEAASPEEIQRYYVALRHYYNWLTRQRY-NH2 (wherein iVal is 3-methylbutanoyl (—C(O)CH 2 CH (CH 3 ) 2 ) C18DA stands for 17-carboxyheptadecanoyl; gGlu represents L-γ-glutamyl connected through its amino group to C18DA and through its γ-carboxy group to Ahx; Ahx represents 6-amino-hexanoyl connected through its amino group to gGlu and through its carboxy group to the ε-amino group of lysine (K). The PYY analogue of any one of claims 1 to 8, which does not include:

20. The PYY analogue of any one of claims 1 to 3, wherein X11 is selected from the group consisting of Asp and GIu.

21. A pharmaceutical composition comprising at least one PYY analogue according to any one of claims 1 to 20.

22. 22. A pharmaceutical composition according to claim 21 for use in a method of medical treatment.

23. 23. A pharmaceutical composition according to claim 21 or 22 for use in the treatment of obesity or an obesity-related condition or disease.

24. 23. The pharmaceutical composition of claim 21 or 22 for use in the treatment of atherogenic dyslipidemia, fatty liver, NAFLD, NASH, renal failure, or atherosclerosis.

25. The pharmaceutical composition of any one of claims 21 to 24, wherein the PYY analogue is administered as part of a combination therapy with an agent for the treatment of diabetes, obesity, dyslipidemia, or hypertension.

26. 26. The pharmaceutical composition of any one of claims 21 to 25, wherein the PYY analogue is administered as part of a combination therapy together with an agent for the treatment of obesity, the agent for obesity being a GIP or GLP-1 receptor agonist, or a glucagon-GLP-1 dual agonist, a GLP-1 / GIP dual agonist, or a GLP-1 / GIP / glucagon triple agonist, or an amylin receptor agonist.

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