Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

1. A monocyclic peptide, comprising the amino acid sequence of Formula (I):

X3-Pen-N-T-X7-Lys(Ac)-Pen-X10-2Nal-X12-E-N—X15-Sarc  (I)

wherein:

X3 is absent or any amino acid;

X7 is Trp, 7-methyl tryptophan (W(7-Me)), or 7 phenyl tryptophan (W(7-Ph));

X10 is Phe(4-(2-aminoethoxy));

X12 is 4-amino-4-carboxy-tetrahydropyran (THP); and

X15 is 3-pyridyl substituted alanine (3Pal); or

a pharmaceutically acceptable salt thereof;

wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond.

2. The monocyclic peptide of claim 1 , comprising the amino acid sequence of Formula (Z′):

R1-X3-Pen-N-T-X7-Lys(Ac)-Pen-X10-2Nal-X12-E-N-3Pal-Sarc-R2  (Z′)

wherein:

R1 is hydrogen or Ac;

X3 is absent or (D)Arg;

X7 is Trp, W(7-Ph), or W(7-Me);

X10 is Phe(4-(2-aminoethoxy));

X12 is THP; and

R2 is NH 2 ; or

a pharmaceutically acceptable salt thereof.

3. The monocyclic peptide of claim 2 , wherein R1 is Ac; or a pharmaceutically acceptable salt thereof.

4. The monocyclic peptide of claim 2 , wherein:

R1 is Ac;

X3 is absent; and

X7 is W(7-Ph);

or a pharmaceutically acceptable salt thereof.

5. A monocyclic peptide comprising the amino acid sequence selected from the group consisting of:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH 2 (SEQ ID NO:104);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH 2 (SEQ ID NO:158); and

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH 2 (SEQ ID NO:247);

or a pharmaceutically acceptable salt thereof;

wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond.

6. The monocyclic peptide of claim 5 , wherein the monocyclic peptide has the structure:

a pharmaceutically acceptable salt thereof.

7. The monocyclic peptide of claim 5 , wherein the monocyclic peptide has the structure:

a pharmaceutically acceptable salt thereof.

8. The monocyclic peptide of claim 5 , wherein the peptide comprises the amino acid sequence of:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH 2 (SEQ ID NO:247), and wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond; or a pharmaceutically acceptable salt thereof.

9. The monocyclic peptide of claim 5 , wherein the monocyclic peptide has the structure:

10. The monocyclic peptide of claim 5 , wherein the monocyclic peptide has the structure:

11. The monocyclic peptide of claim 5 , wherein the peptide comprises the amino acid sequence of:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH 2 (SEQ ID NO:247), and wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond.

12. A method for treating a disease or disorder associated with Interleukin 23 (IL-23) or Interleukin 23 Receptor (IL-23R) in a patient in need thereof, comprising administering to the patient

an effective amount of the monocyclic peptide or pharmaceutically acceptable salt thereof of claim 5 ,

wherein the disease or disorder is inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

13. The method of claim 12 , wherein the disease or disorder is psoriasis (PsO).

14. The method of claim 12 , wherein the disease or disorder is psoriatic arthritis (PsA).

15. The method of claim 12 , wherein the disease or disorder is inflammatory bowel disease (IBD).

16. The method of claim 12 , wherein the monocyclic peptide or the pharmaceutically acceptable salt thereof is administered to the patient in need thereof via an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topically, vaginal, or topical, route of administration.

17. The method of claim 16 , wherein the monocyclic peptide or pharmaceutically acceptable salt thereof is administered to the patient in need thereof via an oral, sublingual, buccal, or topical route of administration.

18. The method of claim 13 , wherein the psoriasis (PsO) is plaque psoriasis.

19. A method for treating a disease or disorder associated with Interleukin 23 (IL-23) or Interleukin 23 Receptor (IL-23R) in a patient in need thereof, comprising administering to the patient

an effective amount of the monocyclic peptide or pharmaceutically acceptable salt thereof of claim 6 ,

wherein the disease or disorder is inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

20. The method of claim 19 , wherein the disease or disorder is psoriasis (PsO).

21. The method of claim 19 , wherein the disease or disorder is psoriatic arthritis (PsA).

22. The method of claim 19 , wherein the disease or disorder is inflammatory bowel disease (IBD).

23. The method of claim 19 , wherein the monocyclic peptide or the pharmaceutically acceptable salt is administered to the patient in need thereof via an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topically, vaginal, or topical, route of administration.

24. The method of claim 23 , wherein the monocyclic peptide or pharmaceutically acceptable salt thereof is administered to the patient in need thereof via an oral, sublingual, buccal, or topical route of administration.

25. The method of claim 19 , wherein the disease or disorder is Ulcerative colitis (UC).

26. The method of claim 19 , wherein the disease or disorder is Crohn's Disease (CD).

27. A method for treating a disease or disorder associated with Interleukin 23 (IL-23) or Interleukin 23 Receptor (IL-23R) in a patient in need thereof, comprising administering to the patient an effective amount of the monocyclic peptide or pharmaceutically acceptable salt thereof of claim 7 , wherein the disease or disorder is inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

28. A method for treating a disease or disorder associated with Interleukin 23 (IL-23) or Interleukin 23 Receptor (IL-23R) in a patient in need thereof, comprising administering to the patient an effective amount of the monocyclic peptide or pharmaceutically acceptable salt thereof of claim 8 , wherein the disease or disorder is inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

29. The method of claim 19 , wherein the monocyclic peptide or the pharmaceutically acceptable salt thereof is administered to the patient in need thereof via an oral route of administration.

30. The method of claim 20 , wherein the psoriasis (PsO) is plaque psoriasis.