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

Patent metadata

Field	Value
Publication number	US-2016145306-A1
Application number	US-201514800627-A
Country	US
Kind code	A1
Filing date	Jul 15, 2015
Priority date	Jul 17, 2014
Publication date	May 26, 2016
Grant date	—

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.

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 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-chloro-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, Abu 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, or Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, Ala, hCys, Abu, 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), hTtr, 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)] or 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-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, βhNal, 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-Oally), Tyr(3-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, or 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 or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, 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)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 .- 6 . (canceled)

7 . 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.

8 . (canceled)

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

10 . The peptide inhibitor of claim 9 , 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, Acpc or THP.

11 . The peptide inhibitor of claim 10 , wherein the peptide inhibitor comprises any of the following the 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 ;

Assignees

• Protagonist Therapeutics Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P37/06

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title