# US 10,246,497 B2 · Selective PYY compounds and uses thereof

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- Number: US 10,246,497 B2
- Document ID: US10246497B2
- Status: Granted
- Kind: B2
- Application number: 15/036,201
- Filed: 2014-11-13
- Published: 2016-10-06
- Granted: 2019-04-02
- Earliest claimed: 2013-11-15
- Assignees: Novo Nordisk A/S
- Applicants: Novo Nordisk A/S
- Inventors: Soeren Oestergaard; Kilian Waldemar Conde Frieboes; Birgit Wieczorek; Jens Kaalby Thomsen; Birgitte Schjellerup Wulff; Carsten Jessen
- Web page: https://patentgrep.com/patent/US10246497B2

## CPC

- C07K 14/47: from mammals
- A61K 38/1709: {from mammals}
- A61K 38/22: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/575: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to PYY compounds having the amino acid in the position corresponding to position 30 of hPYY(1-36) substituted with tryptophan and derivatives thereof with a modifying group attached to the position corresponding to position 7 of hPYY(1-36). The compounds of the invention are selective Y2 receptor agonists. 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.

## Claims

### Claim 1

A PYY compound comprising tryptophan at the position corresponding to position 30 of hPYY(1-36) (SEQ ID NO:1), a maximum of 8 amino acid modifications as compared to hPYY(3-36), wherein the PYY compound comprises N(alpha)-methyl-L-arginine at a position corresponding to position 35 of hPYY(1-36) (SEQ ID NO:1), and wherein the positions corresponding to positions 1-2 or 1-3 of hPYY(1-36) (SEQ ID NO:1) are absent, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A PYY compound according to claim 1, wherein the positions corresponding to positions 1-3 of hPYY(1-36) (SEQ ID NO:1) 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.

### Claim 3 (depends on 1)

A PYY compound according to claim 1, wherein the PYY compound comprises lysine at a position corresponding to position 7 of hPYY(1-36) (SEQ ID NO:1) and a modifying group attached to the epsilon amino group of said lysine, wherein said modifying group is defined by A-B-C-; wherein A- is selected from
wherein a is an integer from 12 to 19, b is an integer from 10 to 16, and c is an integer from 10 to 16, and wherein * denotes the attachment point to -B-;
wherein B- is selected from
wherein d is 1 or 2; e is 1 or 2; and f is 2, 3 or 4; and wherein *** denotes the attachment point to A-, and ** denotes the attachment point to -C-; and
wherein -C- is
wherein g is an integer in the range of 1-5, h is an integer in the range of 1-5, i is an integer in the range of 2 to 6, j is an integer in the range of 1 to 6, and wherein **** denotes the attachment point to -B-, and ***** denotes the attachment point to the epsilon amino group of the Lysine residue in the position corresponding to position 7 of hPYY(1-36).

### Claim 4

A PYY compound selected from the following:
[Trp30,NMeArg35]hPYY3-36 (SEQ ID NO:4)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:5)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]-ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:6)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:7)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30, NMeArg35]hPYY(3-36) (SEQ ID NO:8)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[4-[16-(1H-tetrazol-5-yl) -hex adecanoylsulfamoyl]butanoylamino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:9)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]-amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Aib28,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:10)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:11)
4-N{alpha}-(hexanoyl)-7-N{Epsilon}-2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:12)
4-N{alpha}-(3-methyl-pentanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:13)
4-N{alpha}-(3-methyl-pentanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:14)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]butanoyl]amino]-ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:15)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]-[Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:16)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:18))
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:19)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(14-sulfotetradecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:20)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-carboxy- hexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:21)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(14-carboxy-tetracanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:22)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,Gln18,Ile28,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:23)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:24)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:25)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[2- [2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]-ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:26)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[4-[3-[2-[2-[3-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]propoxy]ethoxy]ethoxy]propylamino]-4-oxobutanoyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQNO:27)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[4-[3-[2-[2-[3-[[4-[3-[2-[2-[3-[[(4S)-4-carboxy -4-(16-sulfohexadecanoylamino)butanoyl]amino]propoxy]ethoxy]-ethoxy]propylamino]-4-oxobutanoyl]amino]propoxy]ethoxy]ethoxy]propylamino]-4-oxobutanoyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:28)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[4-[3-[2-[2-[3-[[4-[3-[2-[2-[3-[[4-[3-[2-[2-[3-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]propoxy]-ethoxy]ethoxy]propylamino]-4-oxobutanoyl]amino]propoxy]ethoxy]-ethoxy]propylamino]-4-oxobutanoyl]amino]propoxy]ethoxy]ethoxy]propylamino]-4-oxobutanoyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:29)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[(2S)-2-amino-6-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-amino]hexanoyl]]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:30)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]-ethoxy]ethoxy]acetyl]-[Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:31)
7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Val3,Arg4,Lys7,Gln18,Trp30,NMeArg35]hPYY(3-36) (SEQ ID NO:32)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,D-Asp11,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:33)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,isoAsp11,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:34)
4-N{alpha}-(3-Methylbutanoyl)-7-N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]-ethoxy]acetyl]-[Arg4,Lys7,D-isoAsp11,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:35)
and
4-N{alpha}-(3-Methylbutanoyl)-[Arg4,Gln18,Trp30,NMeArg35]hPYY(4-36) (SEQ ID NO:38)

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a PYY compound according to claim 1, and at least one pharmaceutically acceptable excipient.

### Claim 6 (depends on 1)

A PYY compound according to claim 1, for use as a medicament.

### Claim 7 (depends on 1)

A PYY compound according to claim 1, for use in the treatment and/or prevention of all forms of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases and/or sleep apnoea; and/or for improving lipid parameters, improving β-cell function, and/or for delaying or preventing diabetic disease progression and/or obesity, 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, osteoarthritis and/or urine incontinence.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a PYY compound according to claim 1, a GLP-1 agonist, and at least one pharmaceutically acceptable excipient.

### Claim 9 (depends on 8)

A pharmaceutical composition according to claim 8, wherein the GLP-1 agonist is liraglutide or semaglutide, and wherein the PYY compound is SEQ ID NO:18.

### Claim 10 (depends on 8)

A method of treating diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases and/or sleep apnoea; and/or for improving lipid parameters, improving β-cell function, and/or for delaying or preventing diabetic disease progression and/or eating disorders 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, osteoarthritis and/or urine incontinence comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 8.

### Claim 11 (depends on 4)

A pharmaceutical composition comprising a PYY compound according to claim 4, a GLP-1 agonist, and at least one pharmaceutically acceptable excipient.

### Claim 12

A pharmaceutical composition comprising liraglutide or semaglutide, and the PYY compound of SEQ ID NO:18.