Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases

1. A peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence consisting of Formula (Xa):

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Xa),

wherein

X1 is absent;

X2 is absent;

X3 is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, or absent;

X4 is Pen;

X5 is Dap, Dap(Ac), Gly, Lys, Gln, Arg, Ser, Thr, or Asn;

X6 is Thr;

X7 is Trp;

X8 is Gln;

X9 is Pen;

X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog;

X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl 2 );

X12 is Acpc, Acbc, Acvc, Achc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg, or 4-amino-4-carboxy-tetrahydropyran;

X13 is Cit, Asp, Glu, Lys, Lys(Ac), Asn, or Gln;

X14 is Dab(Ac), Dap(Ac), His, Lys(Ac), Asn, Gln, or Tyr;

X15 is Ala, betaAla, Gly, Asn, Gln, or Ser;

X16 is any amino acid or absent;

X17 is any amino acid or absent;

X18 is any amino acid or absent;

X19 is any amino acid or absent; and

X20 is any amino acid or absent, wherein the peptide inhibitor is cyclized via a disulfide bond between X4 and X9 of the amino acid sequence, and

wherein 2-Nal is L-2-Naphthylalanine, Pen is L-Penicillamine, Dap is L-Diaminopropionic acid, Dap(Ac) is L-Diaminopropionic acid(Ac), 1-Nal is L-1-Naphthylalanine,

Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Achc is 1-aminocyclohexanecarboxylic acid, Aib is 2-aminoisobutyric acid, α-MeLys is alpha-methyl-L-Lysine, α-MeLys(Ac) is alpha-methyl-L-Lysine(Ac), α-MeLeu is alpha-methyl-L-Leucine, α-MeOrn is alpha-methyl-L-Ornathine, α-MeSer is alpha-methyl-L-Serine, α-MeVal is alpha-methyl-L-Valine, Cha is Cyclohexyl-L-alanine, Cit is L-Citrulline, hLeu is L-homoLeucine, Dab(Ac) is L-Diaminobutyric acid(Ac), and betaAla is Beta-alanine.

2. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor comprises an N-terminal Acetyl group.

3. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor comprises a C-terminal NH 2 group.

4. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein X10 is a Phe analog.

5. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 4 , wherein X10 is Phe(4-OMe), Phe(4-CONH 2 ), Phe[4-(2-acetylaminoethoxy) or Phe[4-(2-aminoethoxy)].

6. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein X11 is 2-Nal.

7. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:602) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

8. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:632) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

9. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-N-[betaAla]-NH 2 (SEQ ID NO:639) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

10. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:666) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

11. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:668) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

12. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-[α-MeVal]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:669) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

13. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is a dimer of two peptide monomers: Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α-MeVal]-KNN-NH 2 (SEQ ID NO:530), or a pharmaceutically acceptable salt thereof, wherein each of the peptide monomers is cyclized via a disulfide bond between the Pens, and wherein the peptide monomers are linked by a DiGlycolic acid (DIG) linker.

14. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is a dimer of two peptide monomers: Ac-[Pen]-QTWQ [Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-K-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:531), or a pharmaceutically acceptable salt thereof, wherein each of the peptide monomers is cyclized via a disulfide bond between the Pens, and wherein the peptide monomers are linked by a DiGlycolic acid (DIG) linker.

15. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is a dimer of two peptide monomers: Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:532), or a pharmaceutically acceptable salt thereof, wherein each of the peptide monomers is cyclized via a disulfide bond between the Pens, and wherein the peptide monomers are linked by a DiGlycolic acid (DIG) linker.

16. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is a dimer of two peptide monomers: Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO:534), or a pharmaceutically acceptable salt thereof, wherein each of the peptide monomers is cyclized via a disulfide bond between the Pens, and wherein the peptide monomers are linked by a DiGlycolic acid (DIG) linker.

17. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Cit]-NN-NH 2 (SEQ ID NO: 1048) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

18. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-ENN-NH 2 (SEQ ID NO:1049) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

19. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is: Ac-[Pen]-NTWQ[Pen]-[Phe(CONH 2 )]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH 2 (SEQ ID NO: 1050) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a disulfide bond between the Pens.

20. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is a dimer of two peptide monomers: Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-[Aib]-KNN-NH 2 (SEQ ID NO:535), or a pharmaceutically acceptable salt thereof, wherein each of the peptide monomers is cyclized via a disulfide bond between the Pens, and wherein the peptide monomers are linked by a DiGlycolic acid (DIG) linker.

21. A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1 .