US20210139548A1 - Npy2 receptor agonists - Google Patents

Npy2 receptor agonists Download PDF

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Publication number
US20210139548A1
US20210139548A1 US17/093,680 US202017093680A US2021139548A1 US 20210139548 A1 US20210139548 A1 US 20210139548A1 US 202017093680 A US202017093680 A US 202017093680A US 2021139548 A1 US2021139548 A1 US 2021139548A1
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ethoxy
group
acetamido
hpyy
compound
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Peter Wilhelm HAEBEL
Albert BRENNAUER
Charlotte Stahl MADSEN
Soren Ljungberg PEDERSEN
Stefan Peters
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG reassignment BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUBRA, APS
Assigned to GUBRA, APS reassignment GUBRA, APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MADSEN, Charlotte Stahl, PEDERSEN, SOREN LJUNGBERG
Assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG reassignment BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRENNAUER, ALBERT, PETERS, STEFAN, HAEBEL, PETER WILHELM
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR AND ASSIGNEE NAMES PREVIOUSLY RECORDED ON REEL 054809 FRAME 0398. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
Publication of US20210139548A1 publication Critical patent/US20210139548A1/en
Priority to US18/068,641 priority Critical patent/US12054525B2/en
Priority to US18/751,723 priority patent/US20250002544A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2271—Neuropeptide Y

Definitions

  • the present invention relates to PYY analogues that are neuropeptide Y2 (NPY2) receptor agonists, and to their medical use in the treatment and/or prevention of a variety of diseases, conditions or disorders, such as treatment and/or prevention of excess food intake, excess body weight, obesity, metabolic diseases, and other conditions or disorders related to excess body weight or obesity, e.g. diabetes and cardiovascular diseases.
  • NPY2 neuropeptide Y2
  • Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health.
  • overweight and obesity are major risk factors for a number of chronic diseases, including type 2 diabetes, cardiovascular diseases and cancer.
  • WHO overweight and obesity are no longer considered a problem limited to high income countries but are now dramatically on the rise in low- and middle-income countries.
  • WHO's Global Health Observatory indicate that, in 2016, 39% of women or men aged 18 and over were overweight and 11% of men and 15% of women were obese.
  • First line therapy for overweight and obese patients comprise diet and exercise but often are not sufficiently efficacious.
  • Second line treatment options are bariatric surgery and pharmacotherapy. Available pharmacological treatments seem to lack in efficacy and/or safety, and only a limited number of approved therapies are available in the US and in Europe.
  • NPY Neuropeptide Y; SEQ ID No:1—human sequence
  • PYY Peptide YY; SEQ ID No: 2—human sequence
  • PP Pancreatic Polypeptide; SEQ ID No:3—human sequence
  • PYY is cleaved to PYY(3-36) by dipeptidyl peptidase IV (DPP IV).
  • DPP IV dipeptidyl peptidase IV
  • PYY(3-36) displays increased selectivity for the neuropeptide Y2 receptor over neuropeptide Y1, Y4 and Y5 receptors as compared to PYY(1-36), albeit some Y1 and Y5 affinity is retained. It is believed that PYY or PYY(3-36) exhibits the feeding suppressive action 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).
  • PYY and also PYY(3-36) have a short half-life in the body and show undesirable chemical or physical properties, e.g. low stability. Further, the pharmacologic effect, e.g. its efficacy as body weight lowering agent, seems limited.
  • WO2014/178018 discloses PYY analogues and their ability to reduce food intake in mice.
  • WO2011/033068 and WO2011/058165 disclose long acting Y2 receptor agonists.
  • WO2015/071355, WO2016/198682 and WO2020/092191 relate to PYY compounds, which are selective Y2 receptor agonists.
  • PYY compounds are disclosed comprising a covalently attached substituent or modifying group also referred therein as a protracting moiety.
  • PYY analogues of the present invention generally are soluble around pH 6 and pH 7.
  • the invention provides a PYY analogue, wherein the analogue comprises
  • the PYY analogue comprises
  • the PYY analogue comprises
  • the PYY analogue is in accordance to one of the above embodiments and bears a half-life extending group, which is attached to the epsilon amino group of the lysine at position 7.
  • the PYY analogue is a compound having the formula:
  • 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, or C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl:
  • R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 alkyl; and Z is an amino acid sequence of formula III (SEQ ID NO: 256):
  • the half-life extending group consists of a lipophilic substituent X and a linker U, wherein the linker U is attached to the 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).
  • the lipophilic substituent X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl
  • the linker U consists of one, two or three sub-moieties independently selected from the group consisting of Gly, Glu, ⁇ -Glu, ⁇ -Lys, Ser, and OEG, or independently selected from the group consisting of ⁇ -Glu, and OEG.
  • the PYY analogue is selected from the compounds 1 to 244 described herein.
  • the PYY analogue is in the form of a salt, preferably in the form of a pharmaceutically acceptable salt.
  • the invention further provides a composition comprising a PYY analogue as described herein.
  • the present invention further provides a PYY analogue for use in a method of medical treatment, e.g. for use in the treatment of obesity and various obesity-related conditions, diseases, or disorders such as type 2 diabetes, NAFLD or NASH.
  • the invention provides a PYY analogue of the invention for use in a method of treating, inhibiting or reducing weight gain, promoting weight loss and/or reducing excess body weight.
  • amino acid positions of the PYY analogues are numbered according to the corresponding position in native human PYY having the sequence shown above.
  • a PYY analogue is a peptide comprising an amino acid sequence corresponding to the amino acid sequence of hPYY(3-36).
  • a PYY analogue is a peptide, whose structure is related to PYY, in which one or more amino acid residues have been modified when compared to hPYY(3-36). Possible modifications are substitutions, insertions, or deletions of amino acids at specific positions.
  • a PYY analogue of the invention relates to a peptide that has retained a certain binding affinity (Ki) towards the hNPY2 receptor.
  • PYY analogue comprises the peptide itself, i.e., in a non-ionized state, as well as the peptide in ionized state (e.g. when one or more side chains of its amino acids are ionized, i.e. (de)protonated).
  • a PYY analogue in a non-ionized state is also referred to herein as a non-salt form of the PYY analogue.
  • PYY analogue may also refer to peptides in which a half-life extending group is attached to one or more amino acids of the peptide. In such cases, a side chain of an amino acid bears a covalently attached half-life extending group.
  • PPY analogue also comprises pharmaceutically acceptable salt forms of the PPY analogue, e.g., when the PPY analogue is in an ionized state.
  • the term “pharmaceutically acceptable salt” is intended to indicate a salt which is not harmful to a patient or subject to which the salt in question is administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic salts.
  • “pharmaceutically acceptable salt” refer to derivatives of the disclosed analogues or compounds wherein the parent analogue or compound is modified by making acid or base salts thereof. Examples of acid addition salts include chloride salts, citrate salts and acetate salts.
  • Examples of basic salts include salts, where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R 1 )(R 2 )(R 3 )(R 4 ) + , where R 1 , R 2 , R 3 and R 4 independently will typically designate hydrogen or optionally substituted C 1-6 -alkyl.
  • alkali metal cations such as sodium or potassium ions
  • alkaline earth metal cations such as calcium or magnesium ions
  • substituted ammonium ions such as ions of the type N(R 1 )(R 2 )(R 3 )(R 4 ) +
  • R 1 , R 2 , R 3 and R 4 independently will typically designate hydrogen or optionally substituted C 1-6 -alkyl.
  • Other examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences”,
  • agonist refers to a substance that activates the receptor type in question, typically by binding to it (i.e. as a ligand).
  • amino acids are referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g. Ala or A for alanine, Arg or R for arginine, etc.).
  • C 1-n alkyl wherein n is an integer selected from 2, 3, 4, 5 or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • C 1-5 -alkyl embraces the radicals H 3 C—, H 3 C—CH 2 —, H 3 C—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—, H 3 C—CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH(CH 3 )—CH 2 —, H 3 C—C(CH 3 ) 2 —, H 3 C—CH 2 —CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH 2 —CH(CH 3 )—, H 3 C—CH 2 —CH(CH 3 )—CH 2 —, H 3 C—CH(CH 3 )—CH 2 —, H
  • C 3-n -cycloalkyl wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3-6 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C(O) or “C( ⁇ O)” refers to a carbonyl group.
  • treatment and grammatical variants thereof (e.g. “treated”, “treating”, “treat”) as employed in the present context refer to an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival relative to expected survival time if not receiving treatment.
  • a subject e.g.
  • a human in need of treatment may thus be a subject already afflicted with the disease or disorder in question.
  • treatment includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. weight gain or hyperglycemia) relative to the absence of treatment and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.
  • prevention and grammatical variants thereof (e.g., “prevented”, “preventing”, “prevent”) as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, “prevention” may refer to prophylactic or preventive measures.
  • beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable.
  • a subject e.g. a human
  • prevention may thus be a subject not yet afflicted with the disease or disorder in question.
  • prevention thus includes inhibiting or slowing the onset of disease relative to the absence of treatment and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition.
  • a half-life extending group is covalently attached to a functional group of a side chain of an amino acid of the PYY analogue.
  • the half-life extending group comprises or consists of a lipophilic substituent (X) and optionally a linker (U), wherein one end of the linker U (if present) is attached to an amino acid of the PYY analogue and the other end is connected to the lipophilic substituent (—U—X).
  • lipophilic substituents (and other classes of half-life extending moieties) bind albumin and other plasma components in the blood stream, thereby shielding the compound of the invention from renal filtration as well as enzymatic degradation and thus possibly enhancing the half-life of the compound in vivo.
  • the lipophilic substituent may also modulate the potency of the compound as an agonist to the NPY2 receptor or other receptors of the NPY receptor family.
  • the lipophilic substituent X is attached to the linker U via an ester, ether, a sulfonyl ester, a thioester, an amide, an amine, triazole or a sulfonamide.
  • the lipophilic substituent X includes an acyl group, a sulfonyl group, an alkyne, an azide, an N atom, an O atom or an S atom, which forms part of the ester, sulfonyl ester, thioester, triazole, amide, amine or sulfonamide.
  • an acyl group, or an O or N atom in the lipophilic substituent X forms part of an amide or ester with the linker U.
  • the half-life extending group (the linker U thereof, if present) is attached to an amino acid residue of the PYY analogue via an ester, a sulfonyl ester, a thioester, an amide, an amine or a sulfonamide.
  • the half-life extending group (the linker U thereof, if present) includes an acyl group, a sulfonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide.
  • an acyl group, or an O or N atom in the linker U forms part of an amide or ester with the amino acid residue.
  • the lipophilic substituent X may comprise a hydrocarbon chain having from 10 to 24 C atoms, e.g. from 14 to 22 C atoms, e.g. from 16 to 20 C atoms. Preferably, it has at least 14 C atoms, and preferably has 20 C atoms or fewer.
  • the hydrocarbon chain may contain 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • the hydrocarbon chain may be linear or branched and may be saturated or unsaturated. Furthermore, it can include a functional group at the end of the hydrocarbon chain, e.g. a carboxylic acid group, a sulphonic acid group, or a tetrazole group.
  • hydrocarbon chain is preferably substituted with a moiety, which forms part of the attachment to an amino acid residue of the PYY analogue or to the linker U, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom.
  • the hydrocarbon chain is substituted with an acyl group (for the attachment to the linker U), and accordingly the hydrocarbon chain may be part of an alkanoyl group, for example a 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.
  • the linker moiety U may itself comprise one, two, three or more linked sub-moieties (U 1 , U 2 , U 3 , etc).
  • the linker may comprise one or more (e.g. one, two or three) linked amino acid residues, which may each independently be a residue of any naturally occurring or non-naturally occurring amino acid.
  • the linker may comprise one, two or three linked amino acid residues, each of which may independently be a residue of Gly, Pro, Ala, Val, Leu, lie, Cys, Phe, Tyr, His, Lys, Arg, Gln, Asn, ⁇ -Glu, ⁇ -Glu, ⁇ -Lys, Asp, ⁇ -Asp, Ser, Thr, Aib, AEA (2-(2-aminoethoxy)acetic 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 (l-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oic acid), H2N-dPEG(12)-COOH (l-aminomino
  • references to ⁇ -Glu, ⁇ -Lys, and ⁇ -Asp indicate residues of amino acids which participate in bonds via their side chain carboxyl or amine functional groups.
  • ⁇ -Glu, and ⁇ -Asp participate in bonds via their alpha amino and side chain carboxyl groups, while ⁇ -Lys participates via its carboxyl and side chain amino groups.
  • ⁇ -Glu, gGlu and isoGlu are used interchangeably.
  • the linker U comprises or consists of one, two or three independently selected sub-moieties (U 1 , U 2 , U 3 ) selected from the group consisting of Ala, Glu, ⁇ -Glu, Gly, ⁇ -Lys, Ser, OEG and OEG-OEG.
  • Linkers consisting of ⁇ -Glu, ⁇ -Glu- ⁇ -Glu, ⁇ -Glu-OEG, OEG-OEG, ⁇ -Glu- ⁇ -Glu-OEG, ⁇ -Glu-OEG-OEG may be preferred.
  • the invention provides a method of synthesis of a PYY analogue of the invention.
  • the PYY analogues may be manufactured by standard synthetic methods, including standard solid-phase or liquid-phase methodology. Peptides are assembled either stepwise or by merging fragments, and optionally isolated and purified yielding the final peptide product. Synthesis examples are described in numerous publications, including Fields, G. B. et al., “Principles and Practice of Solid-Phase Peptide Synthesis” in Synthetic Peptides, Grant G. A. (ed.), Oxford University Press (2 nd edition, 2002).
  • the invention provides a PYY analogue, wherein the analogue comprises
  • the PYY analogue comprises glutamate at the position corresponding to position 9 of hPYY(3-36).
  • the PYY analogue comprises tyrosine at the position corresponding to position 20 of hPYY(3-36).
  • the PYY analogue comprises tryptophan at the position corresponding to position 30 of hPYY(3-36).
  • the PYY analogue comprises leucine at the position corresponding to position 31 of hPYY(3-36).
  • the PYY analogue comprises arginine or lysine at the position corresponding to position 33 of hPYY(3-36). In some embodiments, the PYY analogue bears a half-life extending group, which is attached to the epsilon amino group of the lysine at position 7.
  • the half-life extending group consists of a lipophilic substituent X and a linker U, wherein the linker U is attached to the amino acid side chain, and X is attached to U.
  • the lipophilic substituent X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl.
  • the linker U comprises one or more sub-moieties, wherein at least one of the sub-moieties is OEG.
  • the linker U consists of one, two or three sub-moieties (U1, U2, U3), wherein the sub-moiety is independently selected from the group consisting of Gly, Glu, ⁇ -Glu, ⁇ -Lys, Ser and OEG.
  • the PYY analogue comprises
  • the PYY analogue comprises threonine at the position corresponding to position 32 of hPYY(3-36).
  • the PYY analogue comprises the sequence WLTRQRY (SEQ ID NO: 259) at its C-terminal end.
  • the PYY analogue bears a half-life extending group, which is attached to the epsilon amino group of the lysine at position 7.
  • the PYY analogue comprises
  • the PYY analogue comprises arginine at the position corresponding to position 25 of hPYY(3-36).
  • the PYY analogue bears a half-life extending group, which is attached to the epsilon amino group of the lysine at position 7.
  • 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.
  • the PYY analogue is a compound having the formula:
  • 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 cycloalkyl:
  • R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 alkyl; and Z is a peptide comprising an amino acid sequence of formula I (SEQ ID NO: 254):
  • the PYY analogue is according to the previous embodiment, wherein none of X5, X6, X8-X19, X21-X24 and X26-X32 is absent.
  • 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-C 3-4 cycloalkyl.
  • R 1 is —C(O)CH 2 CH(CH 3 ) 2 , —C(O)CH 2 -cyclobutyl, —C(O)CH 2 -cyclopropyl.
  • PYY analogues of the present invention bearing alanine at position 4 and lysine at position 7—generally are soluble around pH 6 and pH 7.
  • Peptide therapeutics are usually provided as pharmaceutical liquid formulation in a pre-filled ready-to-use injection device. These peptide formulations for subcutaneous administration have limited application volumes. Therefore, good solubility of the peptides is a requirement for the application in a ready-to-use injection device.
  • a further important aspect is the long-term stability and solubility of the peptides in the liquid formulation.
  • a property of fundamental importance for physical stability is the intrinsic solubility (at a given pH value).
  • a peptide formulation around pH 6.0 is believed to show reduced rates of oxidation (e.g. Cys oxidation, disulphide crosslinking, and oxidation of Trp residues), deamination and aspartate isomerization as compared to a formulation at pH 7.
  • Bak et al. A. Bak, D. Leung, S. E. Barrett, S. Forster, E. D. Minnihan, A. W. Leithead, J. Cunningham, N. Toussaint, L.
  • NPY2 receptor agonists seem attractive partners for combination with other weight reducing therapeutics.
  • NPY2 receptor agonists show enhanced weight loss efficacy with GLP-1 receptor agonists (e.g. WO2005/077072, WO2014/178018, WO2018/081370) or amylin (e.g. WO2006/066024, WO2009/064298).
  • Native amylin and many amylin (or calcitonin) analogues comprise a disulphide bridge.
  • a fix-dose combination of a PYY analogue with an amylin analogue might benefit from the opportunity to formulate at a lower pH where the disulphide bridge of the amylin analogue potentially shows improved stability (e.g. due to reduced intramolecular disulphide bond crosslinking reactions).
  • Long in-vivo half-life is also a beneficial property for agents to reduce food intake in over-weight or obese patients.
  • Compounds with a long-acting profile (as compared to the very short in-vivo half-life of native (human) PYY) reducing the frequency of administration are desirable.
  • the invention relates to PYY analogues being NPY2 receptor agonists.
  • the invention relates to PYY analogues showing selectivity towards the NPY receptor subtype Y2 as compared to Y receptor subtypes Y1, Y4 and Y5.
  • the invention relates to PYY analogues with extended half-live, e.g. with longer half-life than the half-life of hPYY(3-36).
  • the PYY analogues of the invention are suitable for once weekly administration.
  • the invention relates to PYY analogues having high chemical and/or physical stability, e.g. around pH 6 or pH 7.
  • the PYY analogue is a compound having the formula:
  • 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, or C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl:
  • R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 alkyl; and Z is an amino acid sequence of formula II (SEQ ID NO: 255):
  • the half-life extending group consists of a lipophilic substituent X and a linker U, wherein the linker U is attached to the amino acid side chain, and X is attached to U, and wherein 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 consists of one, two or three sub-moieties (U1, U2, U3), wherein the sub-moiety is independently selected from the group consisting of Gly, Glu, ⁇ -Glu, ⁇ -Lys, Ser and OEG.
  • the linker U consists of one, two or three sub-moieties (U1, U2, U3), wherein the sub-moiety is independently selected from the group consisting of Gly, Glu, ⁇ -Glu, ⁇ -Lys, Ser and OEG.
  • the PYY analogue is a compound having the formula:
  • 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, or C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl:
  • R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 alkyl; and Z is an amino acid sequence of formula III (SEQ ID NO: 256):
  • the PYY analogue is a compound according to formula I to III, wherein at least two amino acids from X6, X10, X11, X13 and X23 are selected from the group consisting of Asp and Glu.
  • the PYY analogue is a compound according to any of the previous embodiments, wherein only one of X6, X10 and X15 is Ala.
  • the PYY analogue is a compound having the formula:
  • 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, or C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl:
  • R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 alkyl; and Z is an amino acid sequence of formula IV (SEQ ID NO: 257):
  • the PYY analogue is a compound according to formula IV, wherein at least 2 amino acid from X6, X10, X11, X13 and X23 are selected from Asp or Glu.
  • the PYY analogue is a compound according to formula IV, wherein only one of X6, and X10 is Ala.
  • the PYY analogue is a compound according to any of the previous embodiments, wherein X6 is Ala.
  • R 1 is hydrogen, —C(O)C 1-6 alkyl, —C(O)C 3-6 cycloalkyl, or C 1-6 alkyl.
  • R 1 is hydrogen or —C(O)C 1-6 alkyl.
  • R 1 is hydrogen or —C(O)C 1-4 alkyl.
  • R 1 is —C(O)CH 2 CH(CH 3 ) 2 .
  • R 2 is NH 2 .
  • the PYY analogue is a compound having the formula:
  • R 1 and R 2 are defined as in any of the definitions above; and Z is an amino acid sequence selected from Table 1:
  • the PYY analogue is a compound having the formula:
  • R 1 and R 2 are as defined above;
  • Z is an amino acid sequence of selected from Table 1; and wherein a 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, wherein the linker U is attached to the 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).
  • the lipophilic substituent, X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl.
  • the linker U consists of one, two or three sub-moieties (U 1 , U 2 , U 3 ) independently selected from the group consisting of Gly, Glu, ⁇ -Glu, ⁇ -Lys, Ser and OEG, or independently selected from the group consisting of ⁇ -Glu and OEG.
  • the linker U is selected from the group consisting of ⁇ -Glu, ⁇ -Glu- ⁇ -Glu, ⁇ -Glu-OEG, OEG-OEG, ⁇ -Glu- ⁇ -Glu-OEG, ⁇ -Glu-OEG-OEG.
  • the half-life extending group is C18DA- ⁇ -Glu-OEG-OEG-, i.e.
  • the PYY analogue is a compound selected from the group consisting of compound 1 to compound 244 as defined below.
  • the PYY analogue has a maximum of 15 amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has a maximum of 14 amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has a maximum of 13 amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has a maximum of 12 amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has a maximum of 11 amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 7 and 15 (i.e. 7, 8, 9, 10, 11, 12, 13, 14 or 15) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 8 and 14 (i.e. 8, 9, 10, 11, 12, 13 or 14) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 5 and 13 (i.e. 5, 6, 7, 8, 9, 10, 11, 12 or 13) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 7 and 13 (i.e. 7, 8, 9, 10, 11, 12 or 13) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 8 and 13 (i.e. 8, 9, 10, 11, 12 or 13) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 9 and 13 (i.e. 9, 10, 11, 12 or 13) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 10 and 13 (i.e. 10, 11, 12 or 13) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 8 and 12 (i.e. 8, 9, 10, 11 or 12) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 9 and 12 (i.e. 9, 10, 11 or 12) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 10 and 12 (i.e. 10, 11 or 12) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 9 and 11 (i.e. 9, 10 or 11) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue has between 11 and 12 (i.e. 11 or 12) amino acid modifications as compared to hPYY(3-36).
  • the PYY analogue or compound of the above-mentioned embodiments is in the form of a salt, preferably in the form of a pharmaceutically acceptable salt.
  • the PYY analogues of the invention are able to bind to the human NPY2 receptor (hNPY2-R).
  • Binding to biological receptors can be measured by appropriate assays known in the art. For instance, binding of PYY analogues to the NPY2 receptor can be evaluated by radio-ligand binding competition assays, e.g. as described in Example 1, below.
  • the binding affinity (Ki) towards hNPY2 receptor is below 100 nM (e.g. 0.01 to 100 nM).
  • the binding affinity (Ki) towards hNPY2 receptor is below 50 nM (e.g. 0.01 to 50 nM).
  • the binding affinity (Ki) towards hNPY2 receptor is below 10 nM (e.g. 0.01 to 10 nM).
  • the binding affinity (Ki) towards hNPY2 receptor is below 5 nM (e.g. 0.01 to 5 nM).
  • the binding affinity (Ki) towards hNPY2 receptor is below 2 nM (e.g. 0.01 to 2 nM).
  • the PYY analogues of the invention activate the human NPY2 receptor, i.e. they are NPY2 agonists.
  • a biological assay which measures intracellular signalling caused by binding of the compound to the relevant receptor.
  • Activation of the NPY2 receptor by compounds of the invention reduces cAMP concentrations effecting intracellular signalling pathways.
  • reduction of cAMP or any other suitable parameter in cells expressing the receptor can be used to monitor agonist activity towards the receptor.
  • suitable assay formats and examples are provided below.
  • EC 50 values may be used as a numerical measure of agonist potency at a given receptor.
  • An EC 50 value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay, e.g. in the assay as described in Example 2, below.
  • the EC 50 towards hNPY2 receptor is below 100 nM (e.g. 0.001 to 100 nM).
  • the EC 50 towards hNPY2 receptor is below 50 nM (e.g. 0.001 to 50 nM).
  • the EC 50 towards hNPY2 receptor is below 10 nM (e.g. 0.001 to 10 nM).
  • the EC 50 towards hNPY2 receptor is below 5 nM (e.g. 0.001 to 5 nM).
  • the EC 50 towards hNPY2 receptor is below 2 nM (e.g. 0.001 to 2 nM).
  • the PYY analogues or compounds of the present invention are generally soluble around pH 7 and 6.
  • solubility There are several techniques known to the skilled person in the art how to determine solubility. One such experiment is described below under Example 3. If specific solubility in mg/ml is provided herein, it is referred to the solubility determination as in Example 3.
  • the solubility of the PYY analogues or compounds of the invention is greater than 1.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 3.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 5.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is equal to or greater than 7.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is equal to or greater than 8.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 1.0 mg/ml around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 5.0 mg/ml around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 7.0 mg/ml around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is equal to or greater than 8.0 mg/ml around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 1.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2) and around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 3.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2) and around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 5.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2) and around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the solubility of the PYY analogues or compounds of the invention is greater than 6.0 mg/ml around pH 6 (e.g. at pH 6.1 ⁇ 0.2) and around pH 7 (e.g. at pH 6.8 ⁇ 0.2).
  • the PYY analogues or compounds of the invention have favourable pharmacokinetic properties.
  • the in-vivo half-life of the PYY analogues or compounds is at least 3 hours in the mouse (NMRI mice, see measurement described in Example 5). In some embodiments, the in-vivo half-life is at least 5 hours in the mouse. In some embodiments, the in-vivo half-life is at least 7 hours in the mouse. In some embodiments, the in-vivo half-life is at least 10 hours in the mouse.
  • the invention further provides a composition comprising a PYY analogue as described above.
  • the composition may be a pharmaceutical composition, and may comprise a pharmaceutically acceptable carrier, excipient or vehicle.
  • the invention further provides a method for the synthesis of a PYY analogue as described above.
  • the method may comprise the steps of synthesising the peptide by solid-phase or liquid-phase methodology, and optionally isolating and/or purifying the final product.
  • the present invention is directed to PYY analogues or a compound according to the above-mentioned embodiments, which are useful in the prevention and/or treatment of a disease and/or condition 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 co-morbidities, such as type 2 diabetes and NASH (non-alcoholic steatohepatitis).
  • a disease and/or condition 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 co-morbidities, such as type 2 diabetes and NASH (non-alcoholic steatohepatitis).
  • the compounds described herein find use, inter alia, in preventing weight gain or promoting weight loss.
  • preventing is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of weight gain.
  • the peptides may cause a decrease in food intake and/or increased energy expenditure, and may have a beneficial effect on glucose control and/or on circulating cholesterol levels, being capable of lowering circulating LDL levels and increasing HDL/LDL ratio.
  • the compounds of the invention can be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, and obesity related sleep apnea.
  • They may also be used for the prevention of conditions or treatment of obesity associated co-comorbidities caused or characterised by inadequate glucose control or dyslipidaemia (e.g. elevated LDL levels or reduced HDL/LDL ratio), Type 2 diabetes, metabolic syndrome, hypertension, atherogenic dyslipidemia, and cardiovascular diseases such as atherosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease, and cancer.
  • dyslipidaemia e.g. elevated LDL levels or reduced HDL/LDL ratio
  • Type 2 diabetes e.g. elevated LDL levels or reduced HDL/LDL ratio
  • metabolic syndrome e.g. elevated LDL levels or reduced HDL/LDL ratio
  • hypertension e.g. elevated LDL levels or reduced HDL/LDL ratio
  • atherogenic dyslipidemia e.g. elevated LDL levels or reduced HDL/LDL ratio
  • cardiovascular diseases such as atherosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease, and cancer.
  • Their effects in these conditions may be as a result of
  • the PYY analogues or compounds according to the above mentioned embodiments are useful in the reduction of food intake, promotion of weight loss, and inhibition or reduction of weight gain. As a result, they may be used for treatment of a variety of conditions, diseases, or disorders in a subject, including, but not limited to, obesity and various obesity-related conditions, diseases, or co-morbidities, such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and cancer.
  • type 2 diabetes such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and cancer.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the subject may be affected by obesity accompanied by at least one weight-related co-morbid condition, such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardio-vascular disease, hepatic steatosis, NAFLD and NASH.
  • weight-related co-morbid condition such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardio-vascular disease, hepatic steatosis, NAFLD and NASH.
  • the PYY analogues may thus be administered to subjects affected by conditions characterised by inadequate control of appetite or otherwise over-feeding, such as binge-eating disorder and Prader-Willi syndrome. It will be clear that the analogues can be used for treatment of combinations of the conditions described.
  • the invention provides a PYY analogue for use in a method of medical treatment, e.g. for treating, inhibiting or reducing weight gain, promoting weight loss and/or reducing excess body weight.
  • Treatment may be achieved, for example, by control of appetite, feeding, food intake, caloric intake and/or energy expenditure.
  • the invention also provides a PYY analogue of the invention for use in a method of treating obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity related sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility.
  • the subject may be affected by obesity accompanied by at least one weight-related co-morbidity, such as type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease, cancer, hepatic steatosis, NAFLD and NASH.
  • the invention also provides a PYY analogue of the invention for use in a method of prevention or treatment of conditions mentioned above.
  • the present invention relates to a PYY analogue or a compound according to the above-mentioned embodiments for use as a medicament.
  • the present invention relates to the use of a PYY analogue or a compound according to the above-mentioned embodiments for the treatment and/or prevention of a disease and/or condition associated with or modulated by NPY2 receptor activation. Furthermore, the present invention relates to the use of a PYY analogue or a compound according to the above mentioned embodiments for the treatment and/or prevention of obesity and various obesity-related conditions, diseases, or co-morbidities, such as type 2 diabetes and NASH (non-alcoholic steatohepatitis) and others as mentioned above.
  • type 2 diabetes and NASH non-alcoholic steatohepatitis
  • the present invention relates to the use of a PYY analogue or a compound according to the above mentioned embodiments for the preparation of a medicament for the treatment and/or prevention of above-mentioned diseases and conditions.
  • the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a PYY analogue or a compound according to the above-mentioned embodiments to a human being.
  • the dose range of the compounds of general formula 1 applicable per week is usually from 0.01 to 100 mg for humans (subcutaneous administration).
  • the actual pharmaceutically effective amount or therapeutic dosage will usually depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease.
  • the compounds will be administered at dosages and in a manner, which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • a PYY analogue of the invention may be administered as part of a combination therapy together with another active agent for the treatment of the disease or disorder in question, e.g. an anti-obesity agent, an anti-diabetic agent, an agent for treatment of metabolic syndrome, an anti-dyslipidemia agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent.
  • another active agent for the treatment of the disease or disorder in question e.g. an anti-obesity agent, an anti-diabetic agent, an agent for treatment of metabolic syndrome, an anti-dyslipidemia agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent.
  • the two active agents may be given together or separately, e.g. as constituents in the same pharmaceutical composition or formulation, or as separate formulations.
  • a peptide of the invention may be used in combination with an anti-obesity agent of known type.
  • the anti-obesity agent may be a GIP or GLP-1 receptor agonist (including GLP-1 or a GLP-1 analogue, exendin-4 or an exendin-4 analogue, any other GLP-1 receptor agonist including Liraglutide (SaxendaTM), Semaglutide, Dulaglutide, Albiglutide, MK-8521, or a glucagon-GLP-1 dual agonist (e.g.
  • a GLP-1/GIP/glucagon triple agonists e.g. NN-9423 or as described in WO2015/067716, WO2016/198624, WO2017/116204, WO2017/116205, WO2018/100134, WO2018/100135.
  • the anti-obesity agent may be amylin or an amylin analogue, e.g. pramlintide, NN-9838, or an amylin (or calcitonin) analogue disclosed in WO2012/168430, WO2012/168431, WO2012/168432, WO2015/040182, WO2015/071229, WO2016/146739, WO2018/046719, or WO2018/172390.
  • an amylin analogue e.g. pramlintide, NN-9838
  • an amylin (or calcitonin) analogue disclosed in WO2012/168430, WO2012/168431, WO2012/168432, WO2015/040182, WO2015/071229, WO2016/146739, WO2018/046719, or WO2018/172390.
  • the anti-obesity agent may be OrlistatTM, SibutramineTM, phentermine, a melanin concentrating hormone receptor 1 antagonist, CCK, leptin analogue, a GOAT inhibitor, a ghrelin-receptor antagonist, a further neuropeptide Y (NPY) analogue, a NPY4 receptor agonist, a NPY5 receptor antagonist, a cannabinoid receptor 1 antagonist, a beta-3 agonist, a lipase inhibitor, Human prolslet Peptide (HIP), a melanocortin receptor 4 agonist, as well as analogues thereof.
  • NPY neuropeptide Y
  • a peptide of the invention may have some benefit if administered in combination with an anti-diabetic agent of known type, including, but not limited to, metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, a GLP-1 receptor agonist (including GLP-1 or a GLP-1 analogue, an exendin-4 or an exendin-4 analogue, any other GLP-1 receptor agonist including Liraglutide (VictozaTM), Semaglutide, Dulaglutide, Albiglutide, MK-8521, or a glucagon-GLP-1 dual agonist (e.g.
  • a SGLT2 inhibitor i.e. an inhibitor of sodium-glucose transport, e.g.
  • a gliflozin such as empagliflozin, canagliflozin, dapagliflozin or ipragliflozin
  • a GPR40 agonist FFAR1/FFA1 agonist, e.g. fasiglifam
  • insulin analogues include, but are not limited to, LantusTM, NovorapidTM, HumalogTM, NovomixTM ActraphaneTM HM, LevemirTM DegludecTM and ApidraTM.
  • GLP-1 receptor agonists such as exenatide (ByettaTM and BydureonTM exendin-4) and Byetta LARTM, and lixisenatide (LyxumiaTM).
  • the PYY analogue of the present invention is administered as part of a combination therapy together with
  • a peptide of the invention may further be used in combination with medications targeting cardiovascular diseases treating hypertension, dyslipidemia, inflammation and platelet function.
  • the medication treating hypertension can be selected from the group including, but not limited to, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker or a calcium channel blocker.
  • a peptide of the invention may still further be used in combination with an anti-dyslipidemia agent of known type, including, but not limited to, a statin, a fibrate, a niacin, a PSCK9 (Proprotein convertase subtilisin/kexin type 9) inhibitor, or a cholesterol absorption inhibitor.
  • an anti-dyslipidemia agent of known type, including, but not limited to, a statin, a fibrate, a niacin, a PSCK9 (Proprotein convertase subtilisin/kexin type 9) inhibitor, or a cholesterol absorption inhibitor.
  • a peptide of the invention may also be used in combination with a proton pump inhibitor (i.e. a pharmaceutical agent possessing pharmacological activity as an inhibitor of H + /K + -ATPase) of known type, including, but not limited to, an agent of the benzimidazole derivative type or of the imidazopyridine derivative type, such as OmeprazoleTM LansoprazoleTM, DexlansoprazoleTM, EsomeprazoleTM, PantoprazoleTM, RabeprazoleTM ZolpidemTM, AlpidemTM, SaripidemTM or NecopidemTM
  • a proton pump inhibitor i.e. a pharmaceutical agent possessing pharmacological activity as an inhibitor of H + /K + -ATPase
  • an agent of the benzimidazole derivative type or of the imidazopyridine derivative type such as OmeprazoleTM LansoprazoleTM, DexlansoprazoleTM, EsomeprazoleTM,
  • a peptide of the invention may be beneficial if administered in combination with an anti-inflammatory agent of known type, including, but not limited to:
  • steroids and corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (e.g.
  • alminoprofen benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, 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, oxpinac, sulindac, tiopinac, 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.
  • oxicams e.g. isoxicam, piroxicam, sudoxicam and tenoxicam
  • salicylates e.g. acetylsalicylic acid and sulfasalazine
  • pyrazolones e.g. apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone
  • COX II inhibitors such as rofecoxib and celecoxib
  • preparations of interferon beta e.g. interferon beta-la or interferon beta-1b
  • certain other compounds such as 5-aminosalicylic acid and prodrugs and pharmaceutically acceptable salts thereof.
  • the L-form of the amino acid building blocks was utilized if not specified otherwise.
  • the modular half-life extending group was built up 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-[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) and Fmoc-Glu-OtBu.
  • SPPS solid-phase peptide synthesis
  • the PYY analogues were obtained as TFA salts from the cleavage/deprotection or from the HPLC purification.
  • the trifluoroacetate can be exchanged by common procedures, such as resin-ion exchange procedures, e.g. as disclosed in Roux, St. et al. J. Pept. Sci. 2008; 14: 354-359.
  • Peptides were synthesized by microwave-assisted solid-phase peptide synthesis (SPPS) on a CEM Liberty Blue Peptide Synthesizer at 0.25 mmol scale on Tentagel S RAM resin using the Fmoc strategy.
  • SPPS microwave-assisted solid-phase peptide synthesis
  • Standard coupling of amino acids was performed with 4 eq of suitably protected amino acid in DMF (0.2 mol/l, 5 ml), 4 eq of Oxyma in DMF (1 mol/l, 1 ml) and 8 eq DIC in DMF (1 mol/l, 2 ml) at 90° C. for 4 min.
  • Fmoc-Arg(Pbf)-OH was coupled 2 times at 90° C. for 4 min
  • Fmoc-His(Trt)-OH was coupled 2 times at 50° C. for 12 min
  • Fmoc-Glu-OtBu was coupled 4 times at 50° C. for 12 min.
  • Fmoc-OEG-OH, Fmoc-OEG-OEG-OH and C18DA(tBu) were coupled 2 times for 4 min at 90° C.
  • Capping of the N-terminus was achieved by coupling 3-methylbutanoic acid 3 times at 90° C. for 4 min.
  • N ⁇ Fmoc deprotection was performed with 20% piperidine/DMF (10 ml) for 1 min at 90° C.
  • Deprotection of the Lys(Dde)-group was carried out 2 times with 5% hydrazine hydrate in DMF (10 ml) for 3 min at 90° C.
  • Peptides were synthesized by SPPS on a MultiSynTech SYRO II at 0.2 mmol scale.
  • Standard coupling of amino acids was achieved by using 4 eq of suitably protected amino acids dissolved in 0.5 mol/1 Oxyma-DMF solution (0.5 mol/l, 1.6 ml) and 4.5 eq DIC (0.5 mol/l, 1.8 ml) in DMF.
  • Fmoc-Phe-OH was dissolved in 0.5 mol/1 Oxyma-NMP and 4 eq were used for coupling (0.5 mol/l, 1.6 ml).
  • Coupling time of the first 15 amino acids starting from the C-terminus was 2 h at RT. Subsequent couplings were realized by double coupling (2 ⁇ 2 h at RT). Capping of the N-terminus was achieved by coupling with 3-methylbutanoic acid (2 ⁇ 2 h at RT). Deprotection of Lys(Dde)-group was carried out selectively using 5% hydrazine in DMF (5 ⁇ 5 min at RT, 4 ml) followed by coupling of 4eq Fmoc-OEG-OEG-OH (3 ⁇ 2 h at RT), 4 eq Fmoc-Glu-OtBu and 4eq C18DA(tBu) (2 ⁇ 2 h at RT).
  • N ⁇ Fmoc deprotections were performed using 40% piperidine in NMP (4 ml) for 3 min followed by 20% piperidine in NMP (4 ml) for 15 min at RT.
  • Peptides were cleaved from resin and side-chains deprotected by adding 15 ml 95:2:1:2 TFA:DODT:TES:water for 4 h at RT or 45 min at 45° C.
  • the peptides were precipitated with cold diethyl ether, dissolved in acetonitrile/water and purified by preparative HPLC(P02).
  • Peptides were synthesized using microwave-assisted SPPS on a Biotage Alstra Synthesizer at 0.2 mmol scale.
  • Standard coupling of amino acids was achieved by using 5 eq of suitably protected amino acid dissolved in 0.5 mol/1 Oxyma-DMF solution (0.5 mol/l, 2 ml) and 5 eq DIC in DMF (0.5 mol/l, 2 ml). Coupling of the first 15 amino acids starting from the C-terminus was achieved by heating for 5 min to 75° C. Subsequent couplings were realized by double coupling (2 ⁇ 5 min at 75° C.).
  • N ⁇ Fmoc deprotections were carried out using 20% piperidine in DMF for 30 sec followed by 20% piperidine for 3 min at 75° C.
  • Crude peptides were purified by reversed phase chromatography using an Agilent preparative HPLC-MS System with preparative pumps 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 ⁇ , 5 ⁇ m, OBD, 30 mm ⁇ 150 mm) served as stationary phase.
  • the mobile phase was run with a gradient of buffer A (0.1% TFA in H 2 O) and buffer B (0.1% TFA in ACN, gradient: 20-42% over 44 min) at a flow rate of 50 ml/min at 40° C.
  • the relevant fractions were pooled and lyophilized.
  • the final product was characterized by analytical HPLC-MS (A01).
  • Crude peptides were purified by reversed phase HPLC using a Waters preparative HPLC with C8 column (Reprosil Gold 200 ⁇ , 5 ⁇ m, 40 mm ⁇ 250 mm), preparative pumps (waters 2545), UV/VIS detector (Waters 2489) and a Waters fraction collector III.
  • the mobile phase was run with a gradient of buffer A (0.1% TFA in H 2 O) and buffer B (0.1% TFA in ACN, gradient: 35-45% B over 10 min) at a flow rate of 50 ml/min at RT. Relevant fractions were analysed, pooled and lyophilized. The final product was characterized by analytical UPLC-MS (A02).
  • Peptide purity and mass were determined by analytical HPLC-MS on a Kinetex C8 column (Phenomenex, 100 ⁇ , 2.6 ⁇ m, 4.6 mm ⁇ 150 mm) using a Waters Acquity HPLC System equipped with 3100 Mass Detector. Analysis was performed by gradient elution with buffer A (0.3% TFA in H 2 O) 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.
  • Analytical UPLC-MS was performed on a Waters Acquity class H using a Waters Acquity UPLC C18 column (peptide CSHTM 130A, 1.7 ⁇ m, 2.1 mm ⁇ 100 mm) and a gradient flow of buffer C (0.3% TFA in H 2 O) and buffer D (10% H 2 O+0.3% TFA in ACN; 38-48% D over 14 min) connected to a SQ Detector 2 (ESI, Waters).
  • ACN acetonitrile Boc: tert-butyloxycarbonyl
  • C18DA(tBu) 18-(tert-butoxy)-18-oxooctadecanoic acid
  • DPBS Dulbecco's phosphate-buffered saline
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • Dde (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl

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