Selective PYY compounds and uses thereof

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.

2. 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.

3. 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).

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)

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

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

7. 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.

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

9. 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.

10. 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 .

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

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