ORAL PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR AND THEIR USE TO TREAT INFLAMMATORY BOWEL DISEASES

• US 20180022778A1
• Filed: 02/24/2017
• Published: 01/25/2018
• Est. Priority Date: 07/17/2014
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bourne, Gregory, Bhandari, Ashok, Cheng, Xiaoli, Frederick, Brian Troy, Zhang, Jie, Patel, Dinesh V., Liu, David
• Granted Patent: US 10,196,424 B2
• Time in Patent Office: Days
• 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

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 disease.

Claims

1-46. -46. (canceled)

47. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, comprising providing to the subject an effective amount of a pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ir):

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

 

(Ir)

wherein

X1 is any amino acid or absent;

X2 is any amino acid or absent;

X3 is any amino acid or absent;

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu, β

-azido-Ala-OH, propargylglycine, 2-(3′

-butenyl)glycine, 2-allylglycine, 2-(3′

-butenyl)glycine, 2-(4′

-pentenyl)glycine, or 2-(5′

-hexenyl)glycine;

X5 is any amino acid;

X6 is any amino acid;

X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or a corresponding α

-methyl amino acid form of any of the foregoing;

X8 is any amino acid;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu, β

-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2-(3′

-butenyl)glycine, 2-(4′

-pentenyl)glycine, Ala, hCys, Met, MeCys, (D)Tyr or 2-(5′

-hexenyl)glycine;

X10 is Tyr, Phe(4-OMe), 1-Nal, 2-Nal, Aic, α

-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His, hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe(4-CONH₂), Phe(4-phenoxy), Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH₂), Phe(4-F), Phe(3,5-F₂), Phe(4-CH₂CO₂H), Phe(penta-F), Phe(3,4-Cl), Phe(4-CF₃), Bip, Cha, 4-PyridylAlanine, β

hTyr, OctGly, Phe(4-N₃), Phe(4-Br), Phe[4-(2-aminoethoxy)], Phe, a Phe analog, a Tyr analog, or a corresponding α

-methyl amino acid form of any of the foregoing;

X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CO₂H), β

hPhe(4-F), α

-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF₃), Phe(3,4-OMe₂), α

-MePhe, β

hPhe, β

hTyr, β

hTrp, Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-OMe), Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(4-OBzl), Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine or Bip;

X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, α

-MeLys, D-Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, α

-MeLeu, α

-MeOrn, β

-Aib, β

hAla, β

hArg, β

hLeu, β

hVal, β

-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran (THP), Achc Acpc, Acbc, Acvc, Agp, Aib, α

-DiethylGly, α

-MeLys(Ac), α

-MeOrn, α

-MeSer, α

-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys, or a corresponding α

-methyl amino acid form of any of the foregoing;

X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val, β

hAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α

-MeLeu, Aib, β

-Glu, β

hLeu, β

hVal, β

-spiro-pip, Cha, Chg, Asp, Dab, Dap, α

-DiethylGly, hLeu, Asn, Ogl, Pro, Gln, Ser, β

-spiro-pip, Thr, Tba, Tle or Aib, or a corresponding α

-methyl amino acid form of any of the foregoing;

X14 is Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys(Ac), Dap(Ac), Asp, Pro, Gln, Arg, Ser, Thr, Tic or β

hPhe, or a corresponding α

-methyl amino acid form of any of the foregoing;

X15 is Gly, Ser, Thr, Gln, Ala, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, β

-Ala, or Sarc, or a corresponding α

-methyl amino acid form of any of the foregoing;

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 bond between X4 and X9, and

wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

48. The method of claim 47, wherein the pharmaceutical composition is provided to the subject by an oral route of administration.

56. The method of claim 47, wherein the IBD is ulcerative colitis.

57. The method of claim 47, wherein the IBD is Crohn'"'"'s disease.

58. The method of claim 47, wherein the IBD is pouchitis after an ileoanal anastomosis.

59. The method of claim 47, wherein the bond between X4 and X9 is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.

60. The method of claim 47, wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

61. The method of claim 59, wherein

X7 is Trp;

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

X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-Cl₂), Phe(3,4-F₂), Phe(4-CONH₂), or Phe(3,4-Dimethoxy); and

X12 is Aib, α

-Me-Lys, α

-Me-Val, α

-Me-Leu;

Achc, Acvc, Acpc, or 4-amino-4-carboxy-tetrahydropyran (THP).

62. The method of claim 59, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2-aminoethoxy)) or Phe(4-guanidino).

63. The method of claim 59, wherein the peptide inhibitor comprises any of the following amino acid sequences:

64. The method of claim 47, wherein

X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid;

X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys, and

and the bond between X4 and X9 is a thioether bond.

65. The method of claim 64, wherein

(a) X4 is Abu and X9 is Cys;

or

(b) X4 is Cys and X9 is Abu,

wherein the peptide inhibitor is cyclized via a thioether bond between X4 and X9.

66. The method of claim 64, wherein

X7 is Trp;

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

X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-Cl₂), Phe(3,4-F₂), Phe(4-CONH₂), or Phe(3,4-Dimethoxy); and

X12 is α

-Me-Lys, α

-Me-Leu, α

-Me-Ser, α

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

67. The method of claim 66, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2aminoethoxy)) or Phe(4-guanidino)

68. The peptide inhibitor of claim 64, wherein the peptide inhibitor comprises any of the following amino acid sequences:

71. The method of claim 68, wherein the amino acid sequence of the peptide inhibitor comprises one or more, two or more, or three of the following:

X5 is Arg, Gln, Dap or Orn;

X6 is Thr or Ser; and

X8 is Gln, Val, Phe, Glu or Lys.

49-55. -55. (canceled)

69. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, comprising providing to the subject an effective amount of a pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises the amino acid sequence of Formula IIIa:

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

 

(IIIa)

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, Pen, or Cys;

X5 is any amino acid or absent;

X6 is any amino acid or absent;

X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α

-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), β

β

-diPheAla, Phe(4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or a corresponding α

-methyl amino acid form of any of the foregoing;

X8 is any amino acid or absent;

X9 is Abu, Pen, or Cys;

X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly a Phe analog or a Tyr analog, or a corresponding α

-methyl amino acid form of any of the foregoing;

X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(3,4-F₂), β

hPhe(4-F), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α

-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine, α

-MePhe, β

hNal, β

hPhe, β

hTyr, β

hTrp, Bip, Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-Me), Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), or Phe(4-OBzl);

X12 is α

-MeLys, α

-MeOrn, α

-MeLeu, MeLeu, Aib, Achc, Acvc, Acpc, 4-amino-4-carboxy-tetrahydropyran (THP), (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β

-Ala, β

hGlu, β

hAla, β

hLeu, β

hVal, β

-spiro-pip, Cha, Chg, Asp, Dab, Dap, α

-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or a corresponding α

-methyl amino acid form of any of the foregoing;

X13 is Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α

-MeLeu, β

Ala, β

hGlu, β

hAla, β

hLeu, β

hVal, β

-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α

-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α

-methyl amino acid form of any of the foregoing;

X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or a corresponding α

-methyl amino acid form of any of the foregoing;

X15 is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, (2-aminoethoxy)acetic acid (AEA), Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a corresponding α

-methyl amino acid form of any of the foregoing;

X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a corresponding α

-methyl amino acid form of any of the foregoing;

X17 is absent, Glu, Ser, Gly or Gln, or a corresponding α

-methyl amino acid form of any of the foregoing;

X18 is absent or any amino acid;

X19 is absent or any amino acid; and

X20 is absent or any amino acid,

wherein the peptide inhibitor is cyclized via an intramolecular bond between X4 and X9.

70. The method of claim 69, wherein X4 or X9 is Abu.

72. The method of claim 69, wherein the amino acid sequence of the peptide inhibitor comprises one or more, two or more, three or more, four or more, five or more, six or more, or seven of the following:

X10 is Tyr or a Phe analog;

X11 is Trp, 2-Nal, 1-Nal, Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α

-MeTrp or 1,2,3,4-tetrahydro-norharman;

X12 is Arg, hLeu, (D)Asn, Aib, α

-MeLys, α

-MeLeu, α

-MeOrn, Achc, Acvc, Acpc, Acpc, or THP;

X13 is Lys, Glu or Lys(Ac);

X14 is Phe or Asn;

X15 is Gly, Ser, Asn, or Ala; and

X16 is absent.

73. The method of claim 69, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2aminoethoxy)) or Phe(4-guanidino).

74. The method of claim 69, wherein the IBD is Crohn'"'"'s disease.

75. The method of claim 69, wherein the IBD is ulcerative colitis.

76. The method of claim 69, wherein the IBD is pouchitis after an ileoanal anastomosis.

77. The method of claim 69, wherein the peptide inhibitor of the interleukin-23 receptor, or the pharmaceutically acceptable salt or solvate thereof, is provided to the subject orally.