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

• US 10,035,824 B2
• Filed: 12/04/2017
• Issued: 07/31/2018
• Est. Priority Date: 07/17/2014
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Bourne, Gregory, Cheng, Xiaoli, Frederick, Brian Troy, Zhang, Jie, Patel, Dinesh V., Liu, David
• Primary Examiner(s): Ha, Julie
• Application Number:
  US15/831,087
• Publication Number:
  US 20180079782A1
• Time in Patent Office: 239 Days
• Field of Search: 514 132, 514 211, 514 214, 514 215, 514 216, 514 217, 514 218, 530321, 530323, 530326, 530327, 530328, 530329
• CPC Class Codes: 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
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/54 Interleukins [IL]
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/50 Cyclic peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/64 : Cyclic peptides containing only normal peptide links
• CPC Class Codes: G01N 2800/065 : Bowel diseases, e.g. Crohn, ulcerative colitis, IBS

Abstract

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 disease, are disclosed.

Claims

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),

or a pharmaceutically acceptable salt thereof,

wherein

X1 is any amino acid or absent;

X2 is any amino acid or absent;

X3 is any amino acid or absent;

X4 is Abu;

X5 is Gln;

X6 is Thr;

X7 is Trp;

X8 is Gln;

X9 is Cys;

X10 is Phe, Tyr, a Phe analog, or a Tyr analog;

X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl₂);

X12 is α

-Me-Lys, α

-Me-Leu, α

-Me-Ser, α

-Me-Val, Achc, Acvc, Acpc, Acbc, Aib, or 4-amino-4-carboxy-tetrahydropyran;

X13 is any amino acid;

X14 is any amino acid;

X15 is any amino acid,

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 thioether bond between X4 and X9, and

wherein 1-Nal is L-1-napthylalanine, 2-Nal is L-2-napthylalanine, Abu is 2-aminobutyric acid, α

-Me-Lys is alpha-methyl-L-Lysine, α

-Me-Leu is alpha-methyl-L-Leucine, α

-Me-Ser is alpha-methyl-L-Serine, α

-Me-Val is alpha-methyl-L-Valine, Ache is 1-aminocyclohexanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, and Aib is 2-aminoisobutyric acid.

2. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide inhibitor comprises an N-terminal Ac group and a C-terminal NH₂ group.

3. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1, wherein X3 is selected from Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln.

4. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1, wherein X10 is Phe(4-OMe), Phe(4-CONH₂), or Phe[4-(2-aminoethoxy)].

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

6. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQCY-[2-Nal]-[α

-Me-Lys]-ENG-NH₂ (SEQ ID NO;

704) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

7. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe(4-OMe)]-[2-Nal]-[α

-Me-Lys]-ENG-NH₂ (SEQ ID NO;

702) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

8. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]-W-[α

-Me-Lys]-ENG-NH₂ (SEQ ID NO;

782) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

9. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys]-[Lys(isovaleric acid)]-NG-NH₂ (SEQ ID NO;

861) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

10. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-QNG-NH₂ (SEQ ID NO;

877) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

11. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NA-NH₂ (SEQ ID NO;

880) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

12. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys(Ac)]-[Lys(Ac)]-NG-NH₂ (SEQ ID NO;

900) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

13. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys]-ENQ-NH₂ (SEQ ID NO;

911) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

14. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys]-ENN-NH₂ (SEQ ID NO;

912) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

15. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-MeVal]-[Lys(Ac)]-NG-NH₂ (SEQ ID NO;

915) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

16. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Leu)-[Cit]-NN-NH₂ (SEQ ID NO;

954) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

17. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac—

[(D)Phe]-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys]-ENN-NH₂ (SEQ ID NO;

970) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

18. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-T-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α

-Me-Lys]-ENN-NH₂ (SEQ ID NO;

972) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

19. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[acbc]-ENN-NH₂ (SEQ ID NO;

976) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

20. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[acpc]-ENN-NH₂ (SEQ ID NO;

     1043) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

21. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[achc]-ENN-NH₂ (SEQ ID NO;

     1047) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

22. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH₂ (SEQ ID NO;

980) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

23. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[alpha-methyl-L-Leucine]-QN-[betaAla]-NH₂ (SEQ ID NO;

984) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

24. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac-(D)Phe-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH₂ (SEQ ID NO;

992) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

25. The peptide inhibitor or pharmaceutically acceptable salt thereof of claim 3, wherein the peptide inhibitor or pharmaceutically acceptable salt thereof is:

Ac—

[(D)Arg]-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH₂ (SEQ ID NO;

993) or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is cyclized via a thioether bond between Abu and C.

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