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

Patent metadata

Field	Value
Publication number	US-9624268-B2
Application number	US-201514800627-A
Country	US
Kind code	B2
Filing date	Jul 15, 2015
Priority date	Jul 17, 2014
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

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 described.

First claim

What is claimed is:

1. 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 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, 2-(5′-hexenyl)glycine, or absent;
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-CONH 2 ), Phe(4-phenoxy), Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH 2 ), Phe(4-F), Phe(3,5-F 2 ), Phe(4-CH 2 CO 2 H), Phe(penta-F), Phe(3,4-Cl 2 ), Phe(4-CF 3 ), Bip, Cha, 4-PyridylAlanine, βhTyr, OctGly, Phe(4-N 3 ), Phe(4-Br), Phe[4-(2-aminoethoxy)], Phe, 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, Phe(3,4-Cl 2 ), Phe (3,4-F 2 ), Phe(4-CO 2 H), βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF 3 ), Phe(3,4-OMe 2 ), α-MePhe, βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe, His, hPhe, Tic, 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), Octgly, Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH 2 ), Phe(3,4-Dimethoxy), Phe(2,3-Cl 2 ), Phe(2,3-F 2 ), Phe(4-F), 4-phenylcyclohexylalanine or Bip, or a corresponding α-methyl amino acid form of any of the foregoing;
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-Ala, βhAla, βhArg, βhLeu, βhVal, 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, βhAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal, 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 βhPhe, 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.

2. The peptide inhibitor of claim 1 , 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.

3. The peptide inhibitor of claim 1 , wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

4. The peptide inhibitor of claim 3 , wherein
X7 is Trp;
X10 is Phe, Tyr, a Phe analog, or a Tyr analog;
X11 is Trp, 1-Nal or 2-Nal; and
X12 is Aib, α-Me-Lys, α-Me-Val, α-Me-Leu; Achc, Acvc, Acpc, or 4-amino-4-carboxy-tetrahydropyran (THP).

5. The peptide inhibitor of claim 4 , wherein the peptide inhibitor comprises any of the following amino acid sequences:

(SEQ ID NO: 282)

Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-Me-

Lys]-ENG-NH 2 ;

(SEQ ID NO: 283)

Ac-[Pen]-N-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 285)

Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 668)

Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-

[α-MeLys]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 603)

Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLeu]-QNN-NH 2 ;

(SEQ ID NO: 286)

Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe(4-CONH 2 )]-[2-Nal]-

[α-MeLys]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 598)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 1034)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 601)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLys]-ENA-NH 2 ;

(SEQ ID NO: 602)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-

[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 603)

Assignees

• Protagonist Therapeutics Inc

Inventors

• Bourne Gregory Thomas
• Bhandari Ashok
• Cheng Xiaoli
• Frederick Brian Troy
• Zhang Jie
• Patel Dinesh V
• Liu David

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title