WO2016124687A1 - Composés pyy sélectifs et leurs utilisations - Google Patents

Composés pyy sélectifs et leurs utilisations Download PDF

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Publication number
WO2016124687A1
WO2016124687A1 PCT/EP2016/052371 EP2016052371W WO2016124687A1 WO 2016124687 A1 WO2016124687 A1 WO 2016124687A1 EP 2016052371 W EP2016052371 W EP 2016052371W WO 2016124687 A1 WO2016124687 A1 WO 2016124687A1
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ethoxy
amino
hpyy
pyy
acetyl
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PCT/EP2016/052371
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English (en)
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Søren Østergaard
Birgitte Schjellerup Wulff
Kilian Waldemar Conde FRIEBOES
Birgit Wieczorek
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Novo Nordisk A/S
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Publication of WO2016124687A1 publication Critical patent/WO2016124687A1/fr

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    • 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
    • C07K14/575—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine

Definitions

  • the present invention relates to analogues and/or derivatives of Peptide YY
  • PYY is released during a meal from L-cells in the distal small intestine and the colon.
  • PYY is known to have peripheral effects in the gastrointestinal (GI) tract and also act centrally as a satiety signal.
  • PYY is naturally secreted as a 36 amino acid peptide (PYY(l-36)) with a C-terminal amide but is cleaved to PYY(3-36) which constitutes approximately 50% of the circulating PYY.
  • the enzyme responsible for the degradation is dipeptidyl peptidase IV (DPPIV).
  • DPPIV dipeptidyl peptidase IV
  • PYY(3-36) is rapidly eliminated by proteases and other clearance mechanisms.
  • the half-life of PYY(3-36) has been reported to be ⁇ 30 minutes in pigs.
  • PYYY displays suboptimal pharmacokinetic properties, meaning that the peptide has to be administered at least twice daily.
  • PYY(l-36) activates Yl, Y2 and Y5 receptors with very little selectivity and the Y4 receptor slightly less
  • the DPP IV processed PYY(3-36) displays increased selectivity for the Y2 receptor over Yl, Y4 and Y5 receptors, albeit some Yl and Y5 affinity is retained.
  • Y2 receptor activation is known to decrease appetite and food intake whereas Yl and Y5 receptor activation leads to an increase in appetite and food intake.
  • Yl and Y5 receptor activation may lead to an increase in blood pressure.
  • PYY(3-36) has been suggested for use in the treatment of obesity and associated diseases based on the demonstrated effects of certain of these peptides in animal models and in man, and on the fact that obese people have low basal levels of PYY as well as lower meal responses of this peptide. Furthermore, Y2 agonists have been demonstrated to have anti-secretory and pro-absorptive effects in the gastro-intestinal (GI) tract. The potential use of Y2 agonists in the treatment of a number of gastro-intestinal disorders has been suggested. Based on demonstrated effects in e.g. Zucker rats and Diet-Induced Obese (DIO) mice Y2 selective PYY(3-36) analogues have a positive effect on glucose metabolism and are thus suggested to be used for the treatment of diabetes.
  • DIO Diet-Induced Obese
  • WO 2009/138511 relates to long-acting Y2 and/or Y4 receptor agonists.
  • WO 2011/033068 relates to PYY analogues stabilised against C-terminal proteolytic breakdown.
  • WO 2011/058165 relates to Y2 receptor agonists with protracted pharmacokinetic properties.
  • PYY analogues which are specific for the Y receptor subtype Y2 and importantly also display protracted pharmacokinetic properties and as such can be used in a dosing regimen with lower frequency of administration than PYY or PYY(3-36).
  • the invention relates to PYY compounds.
  • the PYY compounds of the present invention have i) tryptophan at the position corresponding to position 30 of hPYY(l-36) (SEQ ID NO : l); ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO: l); iii) lysine at the position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and iv) a modifying group attached to the epsilon amino group of the Lysine residue in position 10, and may comprise up to 10 amino acid modifications as compared to human PYY(3-36) (hPYY(3-36), SEQ ID NO : 2).
  • the invention also relates to pharmaceutical compositions comprising such PYY compounds and pharmaceutically acceptable excipients, as well as the medical use of the PYY compounds.
  • the PYY compounds of the present invention have i) tryptophan at the position corresponding to position 30 of hPYY(l-36) (SEQ ID NO: l); ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l); iii) lysine at the position corresponding to position 10 of hPYY(l-36) (SEQ ID NO: l); iv) glutamine at position corresponding to position 18 of hPYY(l-36) (SEQ ID NO: l);and iv) a modifying group attached to the epsilon amino group of the Lysine residue in position 10, and may comprise up to 10 amino acid modifications as compared to human PYY(3-36) (hPYY(3-36), SEQ ID NO : 2).
  • the invention also relates to pharmaceutical compositions comprising such PYY compounds and pharmaceutically acceptable
  • the invention relates to PYY compounds being Y2 receptor agonists. Also or alternatively, in one aspect, the invention relates to PYY compounds displaying selectivity towards the Y receptor subtype Y2 as compared to Y receptor subtypes Yl, Y4 and Y5.
  • the invention relates to PYY compounds with longer half-life than the half-life of hPYY(3-36). Also or alternatively, in one aspect, the invention relates to PYY compounds with longer half-life than the half-life of hPYY(l-36).
  • the invention relates to PYY compounds.
  • the PYY compounds of the present invention have i) tryptophan at the position corresponding to position 30 of hPYY(l-36) (SEQ ID NO : l); ii) a methyl group added to the a-amino group of the arginine residue in the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), meaning that the residue in the position corresponding to position 35 of hPYY(l-36) is thus N(alpha)- methylarginine; iii) lysine at the position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and iv) a modifying group attached to the epsilon amino group of the Lysine residue in position 10.
  • the PYY compounds of the present invention may comprise up to 10 amino acid modifications as compared to human PYY(3-36) (hPY
  • the PYY compounds of the present invention have i) tryptophan at the position corresponding to position 30 of hPYY(l-36) (SEQ ID NO : l); ii) a methyl group added to the a-amino group of the arginine residue in the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), meaning that the residue in the position corresponding to position 35 of hPYY(l-36) is thus N(alpha)-methylarginine; iii) lysine at the position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); iv) glutamine at position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l); and v) a modifying group attached to the epsilon amino group of the Lysine residue in position 10.
  • the PYY compounds of the present invention may comprise up to
  • the invention relates to PYY compounds being Y receptor subtype Y2 agonists.
  • the invention relates to PYY compounds displaying selectivity towards the Y receptor subtype Y2 as compared to Y receptor subtypes Yl, Y4 and Y5.
  • peptides being "selective" for specific receptors over other receptors refers to peptides that display at least 10 fold, such as at least 20 fold, at least 50 fold, or at least 100 fold higher potency for one Y receptor over other Y receptors as measured in vitro in an assay for receptor function, such as an Actone functional potency assay, and compared by EC50 values, or a Scintillation Proximity Assay (SPA) measuring receptor binding affinity, and compared by Ki values.
  • an assay for receptor function such as an Actone functional potency assay
  • SPA Scintillation Proximity Assay
  • hPYY(l-36) refers to the human Peptide YY, the sequence of which is included in the sequence listing as SEQ ID NO : l.
  • the peptide having the sequence of SEQ ID NO : l may also be designated native hPYY.
  • PYY compound refers to a peptide, or a compound, which is a variant of hPYY(l-36).
  • PYY compound as used herein may also refer to a peptide, or a compound, which is a variant of hPYY(3-36) (SEQ ID NO : 2).
  • PYY compound as used herein may also refer to a peptide, or a compound, which is a variant of hPYY(4-36).
  • the C-terminal of the PYY compounds of the present invention is an amide, as is the C-terminal of native hPYY(l-36) (SEQ ID NO : l) and hPYY(3-36) (SEQ ID NO : 2), respectively.
  • the PYY compounds of the present invention can be PYY analogues and/or derivatives thereof.
  • PYY analogue is used for PYY compounds, where at least one amino acid modification in the backbone is present.
  • PYY derivative is used for PYY compounds comprising at least one non-amino acid substituent covalently attached.
  • a derivative of a PYY analogue is thus a PYY compound comprising at least one amino acid modification and at least one non-amino acid substituent covalently attached.
  • the PYY compounds of the present invention may comprise up to 10 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 9 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 8 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 7 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 6 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 5 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 4 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 3 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • the PYY compounds of the present invention may comprise up to 2 amino acid modifications as compared to hPYY(3-36) (SEQ ID NO : 2).
  • amino acid modification used throughout this application is used in the meaning of a modification to an amino acid as compared to hPYY(3-36). This modification can be the result of a deletion of an amino acid, addition of an amino acid, substitution of one amino acid with another or a substituent covalently attached to an amino acid of the peptide.
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO: l), and iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 7 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 30, 35 and 10 of hPYY(l-36) (SEQ ID NO : l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 6 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO: l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 5 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO: l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 4 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO: l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 3 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO: l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise up to 2 amino acid modifications as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO: l).
  • the PYY compounds of the invention comprises i) tryptophan at the position corresponding to position 30 of hPYY(l-36), ii) N(alpha)-methyl-L-arginine at the position corresponding to position 35 of hPYY(l-36) (SEQ ID NO : l), iii) lysine at a position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and (iv) glutamine at the position corresponding to position 18 of hPYY(l-36) (SEQ ID NO : l), meaning that the PYY compounds of the invention may comprise 1 amino acid modification as compared to hPYY(3-36) in addition to these modification in the positions corresponding to positions 18, 30, 35 and 10 of hPYY(l-36) (SEQ ID NO : l).
  • [Lysl0,Gln l8,Trp30,NMeArg35]hPYY(3-36) comprises 4 amino acid substitutions as compared to hPYY(3-36).
  • [Arg4,Lysl0,Gln l8,Trp30,NMeArg35]hPYY(4-36) comprises 5 amino acid substitutions and 1 deletion as compared to hPYY(3-36), meaning that this compound has 6 amino acid modifications as compared to hPYY(3-36).
  • the PYY peptides of the invention may exhibit at least
  • sequence identity 70%, 75% or 80% sequence identity to hPYY(3-36).
  • sequence identity As an example of a method for determination of the sequence identity between two analogues the two peptides [NMeArg35]hPYY(3-36) and hPYY(3-36) are aligned.
  • the sequence identity of the [NMeArg35]hPYY(3-36) analogue relative to hPYY(3-36) is given by the total number of aligned residues minus the number of different residues (i.e. the number of aligned identical residues) divided by the total number of residues in hPYY(3-36). Accordingly, in said example the sequence identity is (34-l)/34, i.e. 97%.
  • PYY compounds or PYY analogues of the invention may be described by reference to i) the number of the amino acid residue in hPYY(l-36) which corresponds to the amino acid residue which is changed (i.e., the corresponding position in hPYY(l-36), and to ii) the actual change.
  • PYY analogue the position referred to is the position of the PYY analogue corresponding to that particular position of hPYY(l-36).
  • the first amino acid residue of a given sequence is assigned no. 1.
  • the first amino acid residue of hPYY(3-36) which is isoleucine, is assigned no. 3 in the sequence listings.
  • this position is referred to as the position corresponding to position 3 of hPYY(l-36).
  • a PYY compound comprises a particular amino acid at a position corresponding to a certain position of hPYY(l-36), means that the native amino acid in that position has been replaced with that particular amino acid.
  • [NMeArg35]hPYY(3-36) designates an analogue of the human PYY(l-36), wherein the naturally occurring arginine in position 35 has been substituted with N(alpha)- methylarginine (the arginine residue in the position corresponding to position 35 of hPYY(l-36) has a methyl group added to the alpha-amino group) and the naturally occurring tyrosine and proline in position 1 and 2, respectively, have been deleted.
  • [Trp30]hPYY(3-36) designates an analogue of human PYY(3-36), wherein the naturally occurring leucine in the position of hPYY(3-36) corresponding to position 30 of human PYY(l-36) has been substituted with tryptophan.
  • Amino acid residues may be identified by their full name, their one-letter code, and/or their three-letter code. These three ways are fully equivalent.
  • Analogues "comprising" certain specified changes may comprise further changes, when compared to hPYY(l-36). In one aspect, the analogue "has" the specified changes.
  • a PYY analogue is a PYY peptide in which a number of amino acid residues have been modified when compared to hPYY(l-36) or hPYY(3-36). These modifications include substitutions, insertions, and/or deletions, alone or in combination.
  • the PYY analogues of the invention include one or more modifications of a "non-essential" amino acid residue.
  • a "non-essential" amino acid residue is a residue that can be altered, i.e., deleted or substituted in the human PYY amino acid sequence without abolishing or substantially reducing the activity of the PYY analogue towards the Y2 receptor.
  • amino acids may be substituted by conservative substitution.
  • conservative substitution denotes that one or more amino acids are replaced by another, biologically similar residue. Examples include substitution of amino acid residues with similar characteristics, e.g . small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids.
  • the PYY analogues of the invention may comprise substitutions of one or more unnatural and/or non-amino acids, e.g., amino acid mimetics, into the sequence of PYY.
  • the PYY analogues of the invention may have one or more amino acid residues deleted from the amino acid sequence of human PYY, alone or in combination with one or more insertions or substitutions.
  • the PYY analogues of the invention may have one or more amino acid residues inserted into the amino acid sequence of human PYY, alone or in combination with one or more deletions and/or substitutions.
  • the PYY analogues of the invention may include insertions of one or more unnatural amino acids and/or non-amino acids into the sequence of PYY.
  • the PYY peptide may be derived from vertebrates, such as human, mouse, sheep, goat, cow, or horse.
  • vertebrate means members of the subphylum Vertebrata, a primary division of the phylum Chordata that includes the fish, amphibians, reptiles, birds, and mammals, all of which are characterized by a segmented spinal column and a distinct well-differentiated head.
  • mammalia e.g., companion mammals, zoo mammals, and food-source mammals.
  • companion mammals are canines (e.g., dogs), felines (e.g., cats) and horses; some examples of food-source mammals are pigs, cattle, sheep, and the like.
  • the mammal is a human or a companion mammal.
  • the mammal is a human, male or female.
  • the PYY peptides of the invention comprise at least 24 constituent amino acids connected by peptide bonds. In particular embodiments the PYY peptides comprise at least 33 amino acids. In particular embodiments the PYY peptides comprise at least 34 amino acids.
  • Amino acids are molecules containing an amine group and a carboxylic acid group, and, optionally, one or more additional groups, often referred to as a side chain.
  • amino acid includes proteinogenic (or coded or natural) amino acids
  • Non-proteinogenic amino acids are those which are naturally incorporated into proteins.
  • the standard amino acids are those encoded by the genetic code.
  • Non-proteinogenic amino acids are either not found in proteins, or not produced by standard cellular machinery (e.g., they may have been subject to post-translational modification).
  • Non-limiting examples of non-proteinogenic amino acids are Aib (a- aminoisobutyric acid), N(alpha)-methylarginine, as well as the D-isomers of the proteinogenic amino acids.
  • Aib a- aminoisobutyric acid
  • N(alpha)-methylarginine as well as the D-isomers of the proteinogenic amino acids.
  • D-isomer of a proteinogenic amino acid is the D-isomer of aspartic acid, which can also be written as D-Asp.
  • derivative as used herein in the context of a PYY peptide or analogue means a chemically modified PYY peptide, in which one or more substituents have been covalently attached to the peptide.
  • the substituent may be an N-terminal substituent.
  • the substituent may be a modifying group or alternatively, referred to as a protracting moiety.
  • the PYY compound comprises a substituent covalently attached to the alpha-amino group in the amino acid residue in the N-terminus of the PYY compound.
  • the amino acid residues in the positions corresponding to positions 1-3 of hPYY(l-36) are absent, and the N-terminal substituent is covalently attached to the amino acid residue in the position corresponding to position 4 of hPYY(l-36).
  • the N-terminal substituent is an alkoxy group. In one aspect, the N-terminal substituent is an alkoxy group comprising up to 12 carbon atoms. In another aspect, the N-terminal substituent is an alkoxy group comprising up to 6 carbon atoms.
  • the PYY compound comprises a substituent or modifying group covalently attached to the amino acid residue in the position corresponding to position 10 of hPYY(l-36).
  • the substituent or modifying group is capable of forming non-covalent conjugates with proteins, thereby promoting the circulation of the derivative with the blood stream, and also having the effect of protracting the time of action of the derivative, due to the fact that the conjugate of the PYY derivative and albumin is only slowly removed by renal clearance.
  • the substituent, or modifying group, as a whole may also be referred to as a protracting moiety.
  • the modifying group may be covalently attached to a lysine residue of the PYY peptide by acylation, i.e., via an amide bond formed between a carboxylic acid group of the modifying group and the epsilon amino group of the lysine residue.
  • the amino group of lysine could also be coupled to an aldehyde of the modifying group by reductive amination.
  • the thiol group of cysteine could by coupled to a maleiimido group of the modifying group by Michael addition or coupled to the chloro- or iodoacetyl group of the modifying group by nucleophilic substitution.
  • the modifying group is covalently attached to a lysine residue in a position corresponding to position 10 of hPYY(l-36) by acylation, i.e., via an amide bond formed between a carboxylic acid group of the modifying group and the epsilon amino group of the lysine residue.
  • the derivatives of the invention may exist in different stereoisomeric forms having the same molecular formula and sequence of bonded atoms, but differing only in the three-dimensional orientation of their atoms in space.
  • the stereoisomerism of the exemplified derivatives of the invention is indicated in the experimental section, in the names as well as the structures, using standard nomenclature. Unless otherwise stated the invention relates to all stereoisomeric forms of the claimed derivative.
  • the PYY compounds of the invention may be in the form of a pharmaceutically acceptable salt.
  • Salts are e.g. formed by a chemical reaction between a base and an acid, e.g. :
  • the salt may be a basic salt, an acidic salt, or it may be neither nor (i.e. a neutral salt).
  • Basic salts produce hydroxide ions and acid salts hydronium ions in water.
  • the salts of the derivatives of the invention may be formed with added cations or anions between anionic or cationic groups, respectively. These groups may be situated in the peptide moiety, and/or in the side chain of the derivatives of the invention.
  • anionic groups of the derivatives of the invention include free carboxylic groups in the side chain, if any, as well as in the peptide moiety.
  • the peptide moiety often includes free carboxylic groups at internal acid amino acid residues such as Asp and Glu.
  • Non-limiting examples of cationic groups in the peptide moiety include the free amino group at the N-terminus, if present, as well as any free amino group of internal basic amino acid residues such as His, Arg, and Lys.
  • the PYY compounds of the invention have a good Y2 receptor potency. Also, or alternatively, in a second aspect, they bind very well to the Y2 receptor. Preferably they are full Y2 receptor agonists as is reflected by their ability to bind strongly to the Y2 receptor combined with the capacity to fully activate the receptor compared to hPYY(l-36) and hPYY(3-36).
  • the invention relates to PYY compounds displaying selectivity towards the Y receptor subtype Y2 as compared to Y receptor subtypes Yl, Y4 and Y5.
  • the PYY compounds of the invention have improved pharmacokinetic properties. Also, or alternatively, in a fourth functional aspect, the PYY compounds of the invention have increased half-life and/or a decreased clearance. Also, or alternatively, in a fifth functional aspect, they have the effect in vivo of decreasing the blood glucose. Also, or alternatively, in a sixth functional aspect, they have the effect in vivo of decreasing food intake. Also, or alternatively, in a seventh functional aspect, they have the effect in vivo of decreasing body weight.
  • the PYY compounds of the invention are biologically active, or potent.
  • potency and/or activity refers to in vitro potency, i.e. performance in a functional Y2 receptor assay, more in particular to the capability of activating the human Y2 receptor.
  • EC 50 half maximal effective concentration
  • EC 5 o is used as a measure of the potency of a compound and represents the concentration where 50% of its maximal effect is observed.
  • the in vitro potency of the derivatives of the invention may be determined as described in Example 2, and the EC 50 of the derivative in question determined. The lower the EC 50 value, the better the potency.
  • the derivative of the invention has an in vitro potency determined using the method of Example 2 corresponding to an EC 50 at or below 50 nM. In one aspect, the derivative of the invention has an in vitro potency determined using the method of Example 2 corresponding to an EC 50 at or below 30 nM. In one aspect, the derivative of the invention has an in vitro potency determined using the method of Example 2 corresponding to an EC 50 at or below 15 nM .
  • the PYY compounds of the invention bind very well to the Y2 receptor. This may be determined as described in Example 3.
  • Ki the binding to the Y2 receptor should be as good as possible, corresponding to a low Ki value.
  • the Y2 receptor binding affinity (Ki) is below 50 nM. In one aspect of the invention, the Y2 receptor binding affinity (Ki) is below 20 nM . In one aspect of the invention, the Y2 receptor binding affinity (Ki) is below 10 nM .
  • the PYY compounds of the invention are potent in vivo, which may be determined as is known in the art in any suitable animal model, as well as in clinical trials.
  • the diabetic db/db mouse is one example of a suitable animal model, and the blood glucose lowering effect may be determined in such mice in vivo, e.g. as described in Example 5.
  • inhibition of food intake in the db/db mice is a suitable model for determination of effect on food intake and body weight as also described in Example 5.
  • the glucose lowering effect of a 300 nmol/kg dose should be as good as possible corresponding to a low relative % glucose level.
  • 16 hours after dosing (300 nmol/kg) the relative % glucose level is below 90%.
  • 16 hours after dosing (300 nmol/kg) the % relative food intake is below 30%.
  • 4 hours after dosing (300 nmol/kg) the relative % glucose level is below 80.
  • 4 hours after dosing (300 nmol/kg) the % relative food intake is below 20%.
  • the PYY compounds of the invention have improved pharmacokinetic properties such as increased terminal half-life and/or decreased clearance.
  • the pharmacokinetic properties of the derivatives of the invention may suitably be determined in-vivo in pharmacokinetic (PK) studies. Such studies are conducted to evaluate how pharmaceutical compounds are absorbed, distributed, and eliminated in the body, and how these processes affect the concentration of the compound in the body, over the course of time.
  • PK pharmacokinetic
  • animal models such as the mouse, rat, monkey, dog, or pig, may be used to perform this characterisation. Any of these models can be used to test the pharmacokinetic properties of the derivatives of the invention.
  • the estimate of terminal half-life and/or clearance is relevant for evaluation of dosing regimens and an important parameter in drug development, in the evaluation of new drug compounds.
  • the derivatives of the invention have improved pharmacokinetic properties.
  • the pharmacokinetic properties may be determined as terminal half-life (T 1 ⁇ 2 ) in vivo in minipigs after i.v. administration, e.g. as described in Example 4 herein.
  • the terminal half-life in minipigs is at least 15 hours. In one aspect of the invention, the terminal half-life in minipigs is at least 20 hours. In yet another aspect of the invention, the terminal half-life in minipigs is at least 40 hours.
  • the PYY moiety of the derivatives of the invention may for instance be produced by classical peptide synthesis, e.g., solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well established techniques, see, e.g., Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza Dorwald, "Organic Synthesis on solid Phase", Wiley-VCH Verlag GmbH, 2000, and "Fmoc Solid Phase Peptide Synthesis", Edited by W.C. Chan and P.D. White, Oxford University Press, 2000.
  • telomeres may be produced by recombinant methods, viz. by culturing a host cell containing a DNA sequence encoding the analogue and capable of expressing the peptide in a suitable nutrient medium under conditions permitting the expression of the peptide.
  • host cells suitable for expression of these peptides are: Escherichia coli, Saccharomyces cerevisiae, as well as mammalian BHK or CHO cell lines.
  • PYY compounds of the invention which include non-natural amino acids and/or covalently attached substituents may e.g. be produced as described in the experimental part.
  • the PYY compounds of the present invention may be purified by a variety of procedures known in the art including, but not limited to, chromatography (e.g., ion exchange, affinity, hydrophobic, and reverse-phase high performance liquid chromatography (RP-HPLC)), electrophoretic procedures, or extraction (see, e.g., Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989).
  • chromatography e.g., ion exchange, affinity, hydrophobic, and reverse-phase high performance liquid chromatography (RP-HPLC)
  • electrophoretic procedures e.g., electrophoretic procedures, or extraction (see, e.g., Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989).
  • treatment is meant to include both the prevention and minimization of the referenced disease, disorder, or condition (i.e., “treatment” refers to both prophylactic and therapeutic administration of the PYY compounds of the invention or composition comprising the PYY compounds of the invention) unless otherwise indicated or clearly contradicted by context.
  • the route of administration may be any route which effectively transports a compound of this invention to the desired or appropriate place in the body, such as parenterally, for example, subcutaneously, intramuscularly or intravenously.
  • a compound of this invention can be administered orally, pulmonary, rectally, transdermal ⁇ , buccally, sublingually, or nasally.
  • Injectable compositions comprising PYY compounds of the present invention can be prepared using the conventional techniques of the pharmaceutical industry which involve dissolving and mixing the ingredients as appropriate to give the desired end product.
  • a PYY compound of this invention is dissolved in a suitable buffer at a suitable pH so precipitation is minimised or avoided.
  • the injectable composition is made sterile, for example, by sterile filtration.
  • a composition may be a stabilised formulation.
  • stabilized formulation refers to a formulation with increased physical and/or chemical stability, preferably both. In general, a formulation must be stable during use and storage (in compliance with recommended use and storage conditions) until the expiration date is reached.
  • the term "physical stability” refers to the tendency of the polypeptide to form biologically inactive and/or insoluble aggregates as a result of exposure to thermo- mechanical stress, and/or interaction with destabilising interfaces and surfaces (such as hydrophobic surfaces).
  • the physical stability of an aqueous polypeptide formulation may be evaluated by means of visual inspection, and/or by turbidity measurements after exposure to mechanical/physical stress (e.g. agitation) at different temperatures for various time periods.
  • the physical stability may be evaluated using a spectroscopic agent or probe of the conformational status of the polypeptide such as e.g. Thioflavin T or "hydrophobic patch" probes.
  • chemical stability refers to chemical (in particular covalent) changes in the polypeptide structure leading to formation of chemical degradation products potentially having a reduced biological potency, and/or increased immunogenic effect as compared to the intact polypeptide.
  • the chemical stability can be evaluated by measuring the amount of chemical degradation products at various time-points after exposure to different environmental conditions, e.g. by SEC-HPLC, and/or RP-HPLC.
  • the invention provides PYY compounds with improved physical stability. In one aspect, the invention provides PYY compounds with improved chemical stability. COMBINATION TREATMENT
  • the treatment with a PYY compound according to the present invention may also be combined with one or more additional pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • additional pharmacologically active substances e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • GLP-1 receptor agonists examples include insulin, DPP-IV (dipeptidyl peptidase-IV) inhibitors, amylin agonists and leptin receptor agonists.
  • a PYY compound according to the present invention is combined with a GLP-1 agonist.
  • the compounds may be supplied in a single- dosage form wherein the single-dosage form contains both compounds, or in the form of a kit-of-parts comprising a preparation of the PYY compound as a first unit dosage form and a preparation of the GLP-1 agonist as a second unit dosage form.
  • Non-limiting examples of GLP-1 agonists to be combined with the PYY compounds of the present invention are liraglutide, semaglutide, exenatide, dulaglutide, lixisenatide, taspoglutide, and albiglutide.
  • Liraglutide a mono-acylated GLP-1 derivative for once daily administration which is marketed as of 2009 by Novo Nordisk A/S, is disclosed in WO 98/08871.
  • WO 2006/097537 discloses additional GLP-1 derivatives including semaglutide , a mono-acylated GLP-1 derivative for once weekly administration which is under development by Novo Nordisk A/S.
  • Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster. It displays biological properties similar to GLP-1.
  • Dulaglutide is a GLP-l-Fc construct (GLP-1 - linker - Fc from IgG4).
  • Lixisenatide is based on exendin-4(l-39) modified C-terminally with six Lys residues.
  • Taspoglutide is the 8-(2-methylalanine)-35-(2-methylalanine)-36-L-argininamide derivative of the amino acid sequence 7-36 of human GLP-1.
  • Albiglutide is a recombinant human serum albumin (HSA)-GLP-l hybrid protein, likely a GLP-1 dimer fused to HSA.
  • HSA human serum albumin
  • the constituent GLP-1 peptide is an analogue, in which Ala at position 8 has been substituted by Gly.
  • the present invention also relates to a PYY compound of the invention for use as a medicament.
  • the PYY compounds of the invention may be used for the following medical treatments:
  • diabetes prevention and/or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, and/or for reduction of HbAlC;
  • diabetes such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, and/or for reduction of HbAlC;
  • diabetes delaying or preventing diabetic disease progression, such as progression in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin requiring type 2 diabetes, delaying or preventing insulin resistance, and/or delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes;
  • ITT impaired glucose tolerance
  • eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence;
  • eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety
  • treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence;
  • diabetes prevention and/or treatment of diabetic complications, such as angiopathy; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy;
  • a method for altering energy metabolism in a subject.
  • the method includes administering a therapeutically effective amount of a PYY compound of the invention to the subject, thereby altering energy expenditure.
  • Energy is burned in all physiological processes.
  • the body can alter the rate of energy expenditure directly, by modulating the efficiency of those processes, or changing the number and nature of processes that are occurring. For example, during digestion the body expends energy moving food through the bowel, and digesting food, and within cells, the efficiency of cellular metabolism can be altered to produce more or less heat.
  • a method for any and all manipulations of the accurate circuitry described in this application, which alter food intake co-ordinately and reciprocally alter energy expenditure.
  • Energy expenditure is a result of cellular metabolism, protein synthesis, metabolic rate, and calorie utilization.
  • peripheral administration results in increased energy expenditure, and decreased efficiency of calorie utilization.
  • a therapeutically effective amount of a PYY compound according to the invention is administered to a subject, thereby increasing energy expenditure.
  • any subject including those with a body mass index of less than 30, who needs or wishes to reduce body weight is included in the scope of "obese.”
  • the effects of peripherally administered PYY compounds of the present invention in the reduction of food intake, in the delay of gastric emptying, in the reduction of nutrient availability, and in the causation of weight loss are determined by interactions with one or more unique receptor classes in, or similar to, those in the PP family. More particularly, it appears that a receptor or receptors similar to the PYY- preferring (or Y2) receptors are involved.
  • lysine at the position corresponding to position 10 of hPYY(l-36) (SEQ ID NO : l); and iv) a modifying group attached to the epsilon amino group of the Lysine residue in position 10, wherein said modifying group is defined by A-B-C-D-E-, wherein A is selected from
  • a is an integer from 12 to 19
  • b is an integer from 10 to 16
  • c is an integer from 10 to 16;
  • d is 1 or 2; and e is 2, 3 or 4;
  • f is 1 or 2;
  • g is 1 or 2
  • h is 1 or 2
  • E is absent or selected from
  • a is an integer from 12 to 19
  • c is an integer from 10 to 16.
  • c is an integer from 10 to 16.
  • g 1 or 2.
  • h 1 or 2.
  • i is 1 or 2
  • j is 1 or 2.
  • i 1 or 2.
  • a PYY compound according to any one of the preceding embodiments wherein the PYY compound comprises arginine at the position corresponding to position 4 of hPYY( l-36) (SEQ ID NO : l) .
  • the positions corresponding to positions 1 and 2 of hPYY( l-36) (SEQ ID NO : l) are absent.
  • a PYY compound according to any one of the preceding embodiments wherein the positions corresponding to positions 1-3 of hPYY( l-36) (SEQ ID NO : l) are absent, and wherein the PYY compound further comprises an N-terminal substituent, wherein the N-terminal substituent is an alkoxy group comprising up to 12 carbon atoms.
  • a PYY compound according to embodiment 28, wherein the N-terminal substituent is an alkoxy group comprising up to 10 carbon atoms.
  • the N-terminal substituent is an alkoxy group comprising up to 9 carbon atoms.
  • a PYY compound according to embodiment 28, wherein the N-terminal substituent is an alkoxy group comprising up to 8 carbon atoms.
  • the N-terminal substituent is an alkoxy group comprising up to 7 carbon atoms.
  • a PYY compound according to embodiment 28, wherein the N-terminal substituent is an alkoxy group comprising 6 carbon atoms.
  • a PYY compound according to embodiment 1, wherein the PYY compound is compound 10. 70. A PYY compound according to embodiment 1, wherein the PYY compound is compound 11.
  • a PYY compound according to embodiment 1, wherein the PYY compound is compound 22.
  • a PYY compound according to any one of the preceding embodiments which is a full human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is a selective human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is a selective full human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is capable of activating the human Y2 receptor in the Actone functional potency assay of
  • a PYY compound according to any one of the preceding embodiments which has an increased half-life and/or a decreased clearance.
  • a PYY compound according to any one of the preceding embodiments which has the effect in vivo of decreasing the blood glucose determined in a single-dose study in a db/db mouse model.
  • a PYY compound according to any one of the preceding embodiments which has the effect in vivo of decreasing food intake determined in a single-dose study in a db/db mouse model.
  • a pharmaceutical composition comprising a PYY compound according to any one of embodiments 1-97, and at least one pharmaceutically acceptable excipient.
  • a PYY compound according to any one of embodiments 1-97 for use as a medicament.
  • a PYY compound according to any one of embodiments 1-97 for use in the treatment and/or prevention of all forms of diabetes and related diseases, such as eating disorders, diabetic complications, cardiovascular diseases and/or sleep apnoea; and/or for improving lipid parameters, improving ⁇ -cell function, and/or for delaying or preventing diabetic disease progression.
  • a PYY compound according to any one of embodiments 1-97 for use in the treatment and/or prevention of type 2 diabetes.
  • a method of treatment and/or prevention of all forms of diabetes and related diseases such as eating disorders, diabetic complications, cardiovascular diseases and/or sleep apnoea; and/or for improving lipid parameters, improving ⁇ -cell function, and/or for delaying or preventing diabetic disease progression by administering a
  • a method of treatment and/or prevention of type 2 diabetes by administering a pharmaceutically active amount of a PYY compound according to any one of
  • a PYY compound according to any one of embodiments 1-97 in the manufacture of a medicament for the treatment and/or prevention of eating disorders, such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence.
  • eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of
  • a method of treatment and/or prevention of eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence by administering a pharmaceutically active amount of a PYY compound according to any one of embodiments 1-97.
  • a method of treatment and/or prevention of obesity by administering a pharmaceutically active amount of a PYY compound according to any one of
  • A is selected from
  • a is an integer from 12 to 19
  • b is an integer from 10 to 16
  • c is an integer from 10 to 16;
  • g is 1 or 2
  • h is 1 or 2
  • E is absent or selected from
  • a is an integer from 12 to 19
  • c is an integer from 10 to 16.
  • a is an integer from 13 to 15.
  • c is an integer from 10 to 16.
  • i is 1 or 2
  • j is 1 or 2.
  • a PYY compound according to any one of the preceding embodiments wherein the positions corresponding to positions 1-3 of hPYY( l-36) (SEQ ID NO : l) are absent, and wherein the PYY compound further comprises an N-terminal substituent, wherein the N-terminal substituent is an alkoxy group comprising up to 12 carbon atoms.
  • a PYY compound according to embodiment 27, wherein the N-terminal substituent is an alkoxy group comprising up to 7 carbon atoms.
  • the N-terminal substituent is an alkoxy group comprising up to 6 carbon atoms.
  • a PYY compound according to embodiment 27, wherein the N-terminal substituent is selected from 3-methylbutanoyl and 3-methylpentanoyl.
  • a PYY compound according to any one of the preceding embodiments wherein the PYY compound has a maximum of 7 amino acid modifications as compared to hPYY(3-36).
  • the PYY compound has a maximum of 6 amino acid modifications as compared to hPYY(3-36).
  • 41. A PYY compound according to any one of the preceding embodiments, wherein the PYY compound has a maximum of 5 amino acid modifications as compared to hPYY(3-36).
  • a PYY compound according to embodiment 1, wherein the PYY compound is compound 22.
  • a PYY compound according to any one of the preceding embodiments which is a full human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is a selective human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is a selective full human Y2 receptor agonist.
  • a PYY compound according to any one of the preceding embodiments which is capable of activating the human Y2 receptor in the Actone functional potency assay of
  • 93. A PYY compound according to any one of the preceding embodiments which has improved pharmacokinetic properties.
  • a PYY compound according to any one of the preceding embodiments which has an increased half-life and/or a decreased clearance.
  • a PYY compound according to any one of the preceding embodiments which has the effect in vivo of decreasing the blood glucose determined in a single-dose study in a db/db mouse model.
  • a PYY compound according to any one of the preceding embodiments which has the effect in vivo of decreasing food intake determined in a single-dose study in a db/db mouse model.
  • a pharmaceutical composition comprising a PYY compound according to any one of embodiments 1-96, and at least one pharmaceutically acceptable excipient.
  • a PYY compound according to any one of embodiments 1-96 for use as a medicament.
  • a PYY compound according to any one of embodiments 1-96 for use in the treatment and/or prevention of all forms of diabetes and related diseases, such as eating disorders, diabetic complications, cardiovascular diseases and/or sleep apnoea; and/or for improving lipid parameters, improving ⁇ -cell function, and/or for delaying or preventing diabetic disease progression.
  • a PYY compound according to any one of embodiments 1-96 for use in the treatment and/or prevention of type 2 diabetes.
  • a PYY compound according to any one of embodiments 1-96 for the manufacture of a medicament for the treatment and/or prevention of diabetes.
  • 104 Use of a PYY compound according to any one of embodiments 1-96, for the manufacture of a medicament for the treatment and/or prevention of type 2 diabetes.
  • 106. A method of treatment and/or prevention of diabetes by administering a pharmaceutically active amount of a PYY compound according to any one of embodiments 1-96.
  • a method of treatment and/or prevention of type 2 diabetes by administering a pharmaceutically active amount of a PYY compound according to any one of embodiments 1-96.
  • a PYY compound according to any one of embodiments 1-96 for use in the treatment and/or prevention of eating disorders, such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence.
  • a PYY compound according to any one of embodiments 1-96 for use in the treatment and/or prevention of obesity.
  • a PYY compound according to any one of embodiments 1-96 in the manufacture of a medicament for the treatment and/or prevention of eating disorders, such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence.
  • eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of
  • a method of treatment and/or prevention of eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity, such as osteoarthritis and/or urine incontinence by administering a pharmaceutically active amount of a PYY compound according to any one of embodiments 1-96.
  • eating disorders such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/
  • Aib a-aminoisobutanoic acid
  • DIPEA diisopropylethylamine
  • HMWP High molecular weight proteins
  • TIPS triisopropylsilane
  • This section relates to methods for solid phase synthesis of peptide backbone and synthesis of side chain attached to backbone (SPPS methods, including methods for the coupling of amino acids, the de-protection of Fmoc-amino acids, methods for cleaving the peptide from the resin, and for its purification).
  • SPPS methods including methods for the coupling of amino acids, the de-protection of Fmoc-amino acids, methods for cleaving the peptide from the resin, and for its purification).
  • Fmoc- protected amino acid derivatives used were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc- Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Glu-Otbu, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-
  • Fmoc-8-amino-3,6-dioxaoctanoic acid was purchased from Polypeptides, and [N l-(9-Fluorenylmethoxycarbonyl)-l,13-diamino- 4,7,10-trioxatridecan-succinamic (Fmoc-TTDS-OH) was purchased from IRIS Biotech. If nothing else is specified the natural L-form of the amino acids are used.
  • Coupling was done by the use of DIC (dicyclohexylcarbodiimide) and Ozyma Pure (ethyl 2-cyano-2- (hydroxyimino)-acetate, Merck, Novabiochem, Switzerland) mediated couplings in NMP (N-methyl pyrrolidone) .
  • the coupling of the Fmoc-amino acid was done as described above using 4-8 time excess of amino acid relative to resin substitution (4-8 eq). Coupling time ranged from 1 hour up to 4 hours.
  • the Fmoc-Arg(pbf)-OH was coupled using a double coupling procedure (1 hour + 1 hour).
  • the resin used for the synthesis of the peptide amides can be Tentagel RAM (Rapp Polymere, Germany), Rink amid ChemMatrix resin (Matrix Innovation, Canada) Rink-Amide resin (Merck/Novabiochem).
  • the protected amino acid derivatives used were standard Fmoc-amino acids (supplied from e.g. Protein Technologies, or Novabiochem.
  • the epsilon amino group of lysine to be derivatised was protected with Mtt.
  • the N-terminal amino acid or building was coupled as a Boc-protected amino acid, e.g ., Boc-Ile.
  • isovaleric acid was coupled according to the above described coupling procedure for the Fmoc-amino acids.
  • step- wise solid phase assembly on the Prelude was done using the following steps: 1) deprotection (removal of Fmoc) by the use of 25% piperidine in NMP for 2x4 min., step 2) Wash (removal of piperidine) with NMP and DCM, step 3) Coupling of Fmoc-amino acid (0.3M Fmoc-amino acid in 0.3M Oxyma Pure in NMP) 4-8 eq excess for 1-4 hours coupling initiated by adding 1/10 volume of 3M DIC in NMP and 1/10 volume collidine in NMP. Mixing was done by occasional bubbling with nitrogen, step 4) Wash (removal of excess amino acid and reagents by the use of NMP and DCM). Last step included washing with DCM which made the resin ready for attachment of a modifying group on lysine side chain.
  • the building blocks Fmoc-8-amino-3,6-dioxaoctanoic acid (CAS No. 166108-71-0), Fmoc-TTDS-OH (CAS No. 172089-14-4, IRIS Biotech GmbH), Fmoc-L-Glu-OtBu (84793- 07-7), and eicosanedioic acid mono-tert-butyl ester (CAS No. 843666-40-0) were coupled using DIC and Oxyma Pure in 4-8 eq relative to resin substitution.
  • the coupling time was 2-16 hours usually followed by a capping step using 1 M acetic anhydride for 15-60 min.
  • the Fmoc-group was removed by 25% piperidine in NMP for 10-30 min. followed by washing.
  • the 16-sulfonic hexadecanoic acid was solubilised in NMP or N-methylformamid (NMF) at 60 degree Celsius or above and activated by PyBOP 1 eq relative to the sulfonic hexadecanoic acid and 2eq of diisopropylethylamine (DIPEA) relative to sulfonic hexadecanoic acid was also added.
  • DIPEA diisopropylethylamine
  • the peptidyl resin Prior to TFA deprotection the peptidyl resin was washed with DCM or diethyl ether and dried. The peptide and side chain protection groups were removed by addition of 20-40 ml (0.25 mmol scale) 30-60 (0.4 mmol scale) ml 92% TFA, 5% TIPS and 3% H 2 0 for 2-4 hours. Then TFA was filtered and in some cases concentrated by a stream of argon and diethyl ether was added to precipitate the peptide. The peptide was washed three-five times with diethyl ether and dried.
  • Agilent Technologies LC/MSD TOF (G1969A) mass spectrometer was used to identify the molecular weight of the peptide after elution from an Agilent 1200 series HPLC system. The de-convolution of the mass data was calculated using the Agilents software.
  • Buffer A 0.1% TFA in water
  • Solvent A 99.90 % MQ-water, 0.1% formic acid
  • Solvent B 99.90 % acetonitrile, 0.1 % formic acid
  • Buffer B CH3CN + 0.05% TFA
  • Buffer B CH3CN + 0.05% TFA
  • Buffer B CH3CN + 0.05% TFA
  • Buffer A 0.2 M Sodium Sulfate, 0.02 M di-Sodium Hydrogen Phosphate, 0.02 M Sodium di-Hydrogen Phosphate, 90% Water and 10% Acetonitrile, pH 7.2
  • Buffer B 70% Acetonitrile, 30% Water
  • Buffer A 0.2 M Sodium Sulfate, 0.02 M di-Sodium Hydrogen Phosphate, 0.02 M Sodium di-Hydrogen Phosphate, 90% Water and 10% Acetonitrile, pH 7.2
  • Buffer B 70% Acetonitrile, 30% Water
  • Step gradient 10-20% B over 3 minutes, then 20-80% B over 17 minutes, then 80-90% B over 1 minute
  • Buffer A 0.02 M Sodium Sulfate, 0.02 M di-Sodium Hydrogen Phosphate, 0.02 M Sodium di-Hydrogen Phosphate, 90% Water and 10% Acetonitrile, pH 7.2
  • Buffer B 70% Acetonitrile, 30% Water
  • Buffer A 0,1% TFA in H 2 0
  • Buffer B CH3CN + 0,1% TFA
  • Molecular weights of the peptides were determined using matrix-assisted laser desorption time of flight mass spectroscopy (MALDI-MS), recorded on a Microflex (Bruker). A matrix of alpha-cyano-4-hydroxy cinnamic acid was used. The molecular weight of the product was calculated based on the result of MALDI-MS analysis using the software supplied from the manufacturer.
  • MALDI-MS matrix-assisted laser desorption time of flight mass spectroscopy
  • 16-Hexadecanolide (997 g, 3.92 mol) was dissolved in methanol (15.1 L) and toluene-4-sulfonic acid monohydrate (90.0 g, 0.473 mol) was added. Reaction mixture was heated in 50 L reactor at 55 °C for 16 hours. After cooling down sodium hydrogen carbonate (56.0 g, 0.67 mol) was added and the reaction mixture was stirred for 15 min. Solvent was evaporated on Heidolph 20 L rotary evaporator. Ethyl acetate (12 L) was added and the mixture was extracted with 5% solution of sodium hydrogen carbonate (10 L).
  • amino acid sequence of [Lysl0,Glnl8,Aib24,Trp30,NmeArg35]hPYY(3-36) is given SEQ ID NO : 8.
  • amino acid sequence of [Arg4,Lysl0,Gln l8,Trp30,NmeArg35]hPYY(3-36) is given in SEQ ID NO : 10.
  • amino acid sequence of [Arg4,Lysl0,Gln l8,Trp30,NmeArg35]hPYY(4-36) is given in SEQ ID NO : l l .
  • amino acid sequence of [Arg4,l_yslO,Gln l8,Trp30,NmeArg35]hPYY(4-36) is given in SEQ ID NO : l l .
  • amino acid sequence of [Arg4,Lysl0,Gln l8,Trp30,NmeArg35]hPYY(4-36) is given in SEQ ID NO : l l .
  • amino acid sequence of [Arg4,Lysl0,Gln l8,Trp30,NmeArg35]hPYY(4-36) is given in SEQ ID NO : l l .
  • amino acid sequence of [Arg4,Lysl0,Gln l8,Trp30,NmeArg35]hPYY(4-36) is given in SEQ ID NO : l l .
  • PYY peptide derivatives or analogues thereof of the present invention as pharmaceutically active agents in the reduction of weight gain and treatment of obesity in mammals (such as humans), and for treatment of diabetes may be demonstrated by the activity of the agonists in conventional assays and in the in vitro and in vivo assays described below.
  • Such assays also provide a means whereby the activities of the PYY compounds of this invention can be compared with the activities of known compounds.
  • the purpose of this example is to test the activity, or potency, of the PYY compounds in vitro.
  • the in vitro potency is the measure of the activation of the human Yl, Y2, Y4 and Y5 receptor subtypes, respectively, in a whole cell assay.
  • hPYY(3-36) (Example 1.1, SEQ ID NO : 2) was included as a reference.
  • the Neuropeptide Y (NPY) receptors are Gpcoupled seven trans-membrane receptors that mainly signal through the cAMP dependent pathway by inhibiting adenylate cyclase activity which results in a decrease of cAMP production from ATP.
  • the Actone assay is based on a modified calcium channel that has a selective binding for cAMP, resulting in cellular calcium influx, detected by a calcium responsive dye.
  • the ⁇ 1/ ⁇ 2- adrenoreceptor agonist, isoproterenol is added to activate adenylate cyclase and increases cAMP levels in the cell. Decreased cellular calcium concentrations, reflecting a decrease of cAMP levels due to NPY receptor activation, is detected as a decrease in fluorescence from the calcium sensitive dye.
  • HEK-293 cells expressing the cAMP sensitive calcium channel and one of the human NPY receptors Yl, Y2, Y4 or Y5 were seeded into poly lysine coated 384 well plates at a density of 14.000 cells/well (28.000cells/well for Y2 cells) in a volume of 25 ⁇ in DMEM medium containing 10% heat inactivated fetal calf serum (FCS), 1% Penicillin-Streptomycin, 250 ⁇ g/ml aminoglycoside antibiotic G418 and 1 ⁇ g/ml aminonucleoside antibiotic puromycin and 0.1 mM (4S)-4- carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoic acid (or another fatty acid derived compound that binds to albumin's fatty acid binding sites having no affinity to the
  • the cells were incubated over night at +37 °C in a humidified milieu in 5% C0 2 followed by addition of 25 ⁇ calcium dye buffer containing : 1 vial Calcium 5 dye (Molecular Devices, Sunnyvale, CA, USA) solved in 100 ml HBSS buffer containing 20 mM Hepes, 0.1% Ovalbumin, 0.005% Tween 20, 1.5 mM probenecid, 250 ⁇ PDE-inhibitor 4-(3-Butoxy-4- methoxybenzyl)imidazolidin-2-one and 8 mM CaCI 2 and pH was adjusted to 7.40.
  • 1 vial Calcium 5 dye (Molecular Devices, Sunnyvale, CA, USA) solved in 100 ml HBSS buffer containing 20 mM Hepes, 0.1% Ovalbumin, 0.005% Tween 20, 1.5 mM probenecid, 250 ⁇ PDE-inhibitor 4-(3-Butoxy-4- methoxybenzyl)imidazolidin-2-one and 8 mM CaCI 2
  • the PYY compounds of the inventions all display good Y2 potency, whereas the potency on the receptors Yl, Y4 and Y5 is strongly reduced.
  • Example 3 Yl , Y2 f Y4 and Y5 receptor subtype binding
  • the purpose of this example is to test the in vitro binding of the PYY compounds to the Yl, Y2, Y4 and Y5 receptor subtypes, respectively.
  • the receptor binding affinity is a measure of affinity of a compound for the human Yl, Y2, Y4 and Y5 receptor subtypes, respectively.
  • NPY-receptor expressing cell lines All cells were cultured at +37 °C in a humidified atmosphere with 5% C0 2 .
  • BHK-21 clone 6-482-8 cells with inducible expression of the human Yl receptor (P25929, NPYIRJHUMAN, Uniprot) were cultured in Dulbecco's Modified Eagle Medium (DMEM) with 10% heat inactivated fetal bovine serum (FBS), 1% Penicillin-Streptomycin (P/S), 1 mg/ml G418 antibiotic, lmg/ml Hygromycin B antibiotic and 1% Non-essential amino acids.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS heat inactivated fetal bovine serum
  • P/S Penicillin-Streptomycin
  • G418 1 mg/ml G418 antibiotic
  • Hygromycin B antibiotic 1% Non-essential amino acids.
  • CHO-K1 cells stably expressing the human Y2 receptor (P49146, NPY2RJHUMAN, Uniprot) were cultured in DMEM F-12 with 10% FBS, 1% P/S, 150 ⁇ g/ml Hygromycin B and 10 ⁇ g/ml Puromycin antibiotic.
  • CHO-K1 cells stably expressing the human Y4 receptor (P50391, NPY4R_HUMAN, Uniprot) were cultured in DMEM F-12 with 10% FBS, 1% P/S, 10 g/ml Puromycin.
  • HEK-293 cells stably expressing the human Y5 receptor (Q15761, NPY5R_HUMAN, Uniprot) were cultured in DMEM F-12 medium containing 10% FBS, 1% Penicillin-Streptomycin, 250 g/ml G418 and 1 g/ml puromycin.
  • Membrane preparation The preparation.
  • Cultured cells were detached mechanically by scraping and washed in ice cold PBS (137 mM NaCI, 2.7 mM KCI, 4.3 mM Na 2 HP0 4 ,1.47 mM KH 2 P0 4 pH adjusted to 7.4) and transferred to tubes and centrifuged for 5 minutes at 1000 g at +4 °C.
  • PBS 137 mM NaCI, 2.7 mM KCI, 4.3 mM Na 2 HP0 4 ,1.47 mM KH 2 P0 4 pH adjusted to 7.4
  • Pellets were resuspended in ice cold homogenization buffer; Yl : 20 mM Hepes, lOmM EDTA, with 2 complete EDTA-free protease inhibitor cocktail tablets/50 ml (Roche, Mannheim, Germany) pH 7.4); Y2, Y4: 20 mM Hepes, 5mM MgCI 2 , 1 mg/ml Bacitracin, pH 7.1; Y5: 10 mM NaCI, 20 mM Hepes, 0.22 mM KH 2 P0 4 , 1.26 mM CaCI 2 , 0.81 mM MgS0 4 , pH 7.4 and then homogenized for 30 seconds using a tissue homogenizer at medium speed.
  • the homogenate was centrifuged at 35000g using an ultracentrifuge for 10 minutes at +4°C and the supernatant was discarded and fresh homogenization buffer added. Homogenization of the pellet was repeated a total of three times. The final pellet was resuspended in a few millilitres of homogenization buffer and protein concentration was determined using the Bradford method and measured at 595 nm in a microplate reader. Protein concentration were adjusted to lmg/ml and transferred to cryotubes and stored at -80°C. 250 mM sucrose was added to Y5 membranes prior to freezing.
  • 50000 cpm per well of radio ligand human [ 125 I]-PYY(l-36) was added corresponding to a concentration of 100 pM in Yl, Y2 and Y5 binding assays.
  • 50000 cpm per well of radio ligand human [ 125 I]-Pancreatic Polypeptide (PP) corresponding to a concentration of 100 pM was used in Y4 binding assay.
  • Freeze dried analogues were dissolved in 80% dimethyl sulfoxide (DMSO), 19% H 2 0 and 1% acetic acid (CH 3 COOH) to stock solutions of 2000 ⁇ (Y1,Y4 and Y5) and 200 ⁇ (Y2) and serial dilutions (1 : 10) were performed in binding buffer to final concentrations ranging from 10000 nM to 1 pM in the Yl, Y4 and Y5 assays and 1000 nM to 0.1 pM in the Y2 assay.
  • DMSO dimethyl sulfoxide
  • CH 3 COOH acetic acid
  • the PYY compounds of the invention all display good Y2 binding while the binding affinity on the receptors Yl, Y4 and Y5 is strongly reduced.
  • the purpose of this study is to determine the half-life in vivo of the PYY compounds after i.v. administration to minipigs, i.e. the prolongation of their time in the body and thereby their time of action. This is done in a pharmacokinetic (PK) study, where the terminal half-life of the derivative in question is determined.
  • terminal half- life is generally meant the period of time it takes to halve a certain plasma concentration, measured after the initial distribution phase.
  • the animals were weighed weekly. The animals were fasted on the morning prior to dosing but had ad libitum access to water; food was supplied during dosing.
  • Blood samples and analysis Blood samples and analysis. Blood samples were taken through the central catheter according to the following schedule: Predose, 5, 15, 30, 45 min, 1 h, 1.5 h, 2 h,
  • Plasma concentration-time profiles was analysed by a non- compartmental pharmacokinetics analysis using Phoenix (Pharsight Inc., Mountain View, CA, USA). Calculations were performed using individual concentration-time values from each animal. Sample analysis
  • the test substances were assayed in plasma by Turbulent Flow Chromatography coupled to Liquid Chromatography with subsequent Mass Spectrometric Detection (TFC/LC/MS).
  • TFC/LC/MS Turbulent Flow Chromatography coupled to Liquid Chromatography with subsequent Mass Spectrometric Detection
  • the selectivity of the method allowed various compounds to be quantitated in one sample, e.g. cassette dosing of four compounds per animal.
  • the concentrations of the test substance in unknown samples were calculated using the peak area as a function of amount.
  • Calibration graphs based on plasma samples spiked with the analyte were constructed by regression analysis. Typical dynamic range for the assay was 1 - 2,000 nmol/l.
  • the method performance was assured by co-assaying quality control (QC) samples in duplicate at three concentration levels.
  • Stock and working solutions of analytes were prepared in plasma and incubated by 37 °C for 1 hour.
  • Plasma concentration-time profiles was analysed by a non- compartmental pharmacokinetics analysis using Phoenix (Pharsight Inc., Mountain View, CA, USA). Calculations were performed using individual concentration-time values from each animal. Table 3 : Half-life (t 1 / 2 )
  • the tested PYY compounds of the invention have very long half-lives as compared to the half-life of hPYY(3-36).
  • the indicated compound or vehicle 50 mM Na2HP04, pH 7,4, 70 mM NaCI, 0.05% Tween 80
  • Blood glucose and food intake are measured at the indicated time points post injection, e.g at 4 hours (4 h), 16 hours (16 h), 23 hours (23 h) and 40 hours (40 h) post injection.
  • Blood samples for blood glucose are taken from the tail vein, into a 5 ⁇ heparin coated capillary tube which is placed in an eppendorf tube with Biosen ® system solution (250 ⁇ ). The samples are analysed on a Biosen ® instrument immediately.
  • BG Blood glucose
  • Food intake is reported as mean ⁇ SEM food intake per cage as a percentage of average food intake of the vehicle group for the indicated interval.
  • Table 5 Effect on food intake in db/db mice. Food intake is reported as mean ⁇ SEM food intake per cage as a percentage of average food intake of the vehicle group for the indicated interval.

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Abstract

L'invention concerne des composés PYY dont l'acide aminé dans la position correspondant à la position 30 de hPYY(1-36) est substitué par un tryptophane, et des dérivés desdits composés ayant un groupe de modification fixé à la position correspondant à la position 10 de hPYY(1-36). Les composés selon l'invention sont des agonistes sélectifs du récepteur Y2. L'invention concerne également des compositions pharmaceutiques comprenant lesdits composés PYY et des excipients pharmaceutiquement acceptables, ainsi que l'utilisation médicale de ces composés PYY.
PCT/EP2016/052371 2015-02-04 2016-02-04 Composés pyy sélectifs et leurs utilisations WO2016124687A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109248323A (zh) * 2017-07-14 2019-01-22 杭州先为达生物科技有限公司 酰化的glp-1衍生物
CN111944038A (zh) * 2019-04-30 2020-11-17 深圳市健元医药科技有限公司 一种索玛鲁肽的合成方法
CN114206375A (zh) * 2019-08-07 2022-03-18 诺和诺德股份有限公司 包含pyy化合物和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物
US11744873B2 (en) 2021-01-20 2023-09-05 Viking Therapeutics, Inc. Compositions and methods for the treatment of metabolic and liver disorders

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WO2006082517A1 (fr) * 2005-02-04 2006-08-10 Pfizer Products Inc. Agonistes pyy et utilisations de ceux-ci
WO2011033068A1 (fr) * 2009-09-18 2011-03-24 Novo Nordisk A/S Agonistes du récepteur y2 à action prolongée
WO2011058165A1 (fr) * 2009-11-13 2011-05-19 Novo Nordisk A/S Agonistes du récepteur y2 à action prolongée
US20140329742A1 (en) * 2013-05-02 2014-11-06 Glaxosmithkline Intellectual Property (No. 2) Limited Therapeutic peptides

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Publication number Priority date Publication date Assignee Title
WO2006082517A1 (fr) * 2005-02-04 2006-08-10 Pfizer Products Inc. Agonistes pyy et utilisations de ceux-ci
WO2011033068A1 (fr) * 2009-09-18 2011-03-24 Novo Nordisk A/S Agonistes du récepteur y2 à action prolongée
WO2011058165A1 (fr) * 2009-11-13 2011-05-19 Novo Nordisk A/S Agonistes du récepteur y2 à action prolongée
US20140329742A1 (en) * 2013-05-02 2014-11-06 Glaxosmithkline Intellectual Property (No. 2) Limited Therapeutic peptides

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109248323A (zh) * 2017-07-14 2019-01-22 杭州先为达生物科技有限公司 酰化的glp-1衍生物
CN109248323B (zh) * 2017-07-14 2023-09-08 杭州先为达生物科技有限公司 酰化的glp-1衍生物
CN111944038A (zh) * 2019-04-30 2020-11-17 深圳市健元医药科技有限公司 一种索玛鲁肽的合成方法
CN111944038B (zh) * 2019-04-30 2023-06-13 深圳市健元医药科技有限公司 一种索玛鲁肽的合成方法
CN114206375A (zh) * 2019-08-07 2022-03-18 诺和诺德股份有限公司 包含pyy化合物和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物
US11744873B2 (en) 2021-01-20 2023-09-05 Viking Therapeutics, Inc. Compositions and methods for the treatment of metabolic and liver disorders

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