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

Patent metadata

Field	Value
Publication number	US-11845808-B2
Application number	US-202117149509-A
Country	US
Kind code	B2
Filing date	Jan 14, 2021
Priority date	Jan 15, 2020
Publication date	Dec 19, 2023
Grant date	Dec 19, 2023

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.

First claim

What is claimed is:

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.

Assignees

• Janssen Biotech Inc
• Protagonist Therapeutics Inc

Inventors

• Sun Chengzao
• Frederick Brian Troy
• Somani Sandeep
• Bourne Gregory Thomas
• Patch Raymond
• Bhandari Ashok

Classifications

• C07K7/08 Primary

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• A61K38/00

  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) · CPC title

• C07K14/7155

  for interleukins [IL] · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title