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

1. 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, 41-C, 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, 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, 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-CONH 2 ), Phe(3,4-Dimethoxy), Phe(2,3-Cl 2 ), Phe(2,3-F 2 ), 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, 0-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, or hArg, or a corresponding α-methyl amino acid form of any of the foregoing;

X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, 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, Ogl, Pro, Gln, Ser, β-spiro-pip, 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, 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 method of claim 1 , wherein the pharmaceutical composition is provided to the subject by an oral route of administration.

3. The method of claim 1 , wherein the IBD is ulcerative colitis.

4. The method of claim 1 , wherein the IBD is Crohn's disease.

5. The method of claim 1 , wherein the IBD is pouchitis after an ileoanal anastomosis.

6. The method 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.

7. The method of claim 1 , wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

8. The method of claim 6 , 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-Cl 2 ), Phe(3,4-F 2 ), Phe(4-CONH 2 ), 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).

9. The method of claim 6 , wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH 2 ), Phe(3,4-Cl 2 ), Phe(4-tBu), Phe(4-NH 2 ), Phe(4-Br), Phe(4-CN), Phe(4-CO 2 H), Phe(4-(2-aminoethoxy)) or Phe(4-guanidino).

10. The method of claim 1 , 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.

11. The method of claim 1 , 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.

12. The method of claim 11 , 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-Cl 2 ), Phe(3,4-F 2 ), Phe(4-CONH 2 ), 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.

13. The method of claim 12 , wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH 2 ), Phe(3,4-Cl 2 ), Phe(4-tBu), Phe(4-NH 2 ), Phe(4-Br), Phe(4-CN), Phe(4-CO 2 H), Phe(4-(2aminoethoxy)) or Phe(4-guanidino).

14. The method of claim 1 , 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.

15. 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 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]-QTWQ-[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)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNN-NH 2 ;

(SEQ ID NO: 604)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-ENN-NH 2 ;

(SEQ ID NO: 605)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-Aib-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 606)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH 2 ;

(SEQ ID NO: 613)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 614)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNN-NH 2 ;

(SEQ ID NO: 639)

Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-N-[βAla]-NH 2 ;

(SEQ ID NO: 641)

Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[hLeu]-[Lys(Ac)]-N-[βAla]-NH 2 ;

(SEQ ID NO: 616)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 632)

Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 617)

Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH 2 ;

or

(SEQ ID NO: 623)

Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH 2 ,

wherein the peptide inhibitor comprises a disulfide bond between the two Pen amino acids.

16. The method of claim 15 , wherein the IBD is ulcerative colitis.

17. The method of claim 15 , wherein the IBD is Crohn's disease.

18. The method of claim 15 , wherein the IBD is pouchitis after an ileoanal anastomosis.

19. 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 any of the following amino acid sequences:

(SEQ ID NO: 430)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-E-N-G;

(SEQ ID NO: 431)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeOrn]-ENG-NH 2 ;

(SEQ ID NO: 432)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CO 2 H)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 433)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 434)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CONH 2 )]-[2-Nal]-[α-MeLys]-[Lys(Ac)]NG-NH 2 ;

(SEQ ID NO: 435)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NA-NH 2 ;

(SEQ ID NO: 436)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NAE-NH 2 ;

(SEQ ID NO: 437)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG-NH 2 ;

(SEQ ID NO: 439)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-DNG-NH 2 ;

(SEQ ID NO: 440)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(succinic acid)]-

NG-NH 2 ;

(SEQ ID NO: 441)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(glutaric acid)]-

NG-NH 2 ;

(SEQ ID NO: 442)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(pyroglutamic

acid)]-NG-NH 2 ;

(SEQ ID NO: 443)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(isovaleric acid)]-

NG-NH 2 ;

(SEQ ID NO: 444)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-

[(D)Lys]-NH 2 ;

(SEQ ID NO: 445)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-[AEA]-

NH 2 ;

(SEQ ID NO: 446)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-QNG-NH 2 ;

(SEQ ID NO: 447)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NA-NH 2 ;

(SEQ ID NO: 448)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-KNG-NH 2 ;

(SEQ ID NO: 449)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 656)

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

NG-NH 2 ;

(SEQ ID NO: 657)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENG-NH 2 ;

(SEQ ID NO: 658)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-

tetrahydropyran]-ENN-NH 2 ;

(SEQ ID NO: 659)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENQ-NH 2 ;

(SEQ ID NO: 912)

Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 660)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeVal]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 661)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[hLeu]-[Lys(Ac)]-N-[βAla]-NH 2 ;

(SEQ ID NO: 662)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENQ-NH 2 ;

(SEQ ID NO: 663)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENN-NH 2 ;

(SEQ ID NO: 664)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENN-NH 2 ;

(SEQ ID NO: 665)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu)-[Cit]-NN-NH 2 ;

(SEQ ID NO: 766)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH 2 ;

(SEQ ID NO: 767)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NG-NH 2 ;

(SEQ ID NO: 965)

Ac-E-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 966)

Ac-(D)Glu-[Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 967)

Ac-Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 1041)

Ac-[(D)Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 969)

Ac-F-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 970)

Ac-[(D)Phe]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 971)

Ac-[2-Nal]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 973)

Ac-Leu-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 1042)

Ac-[(D)Gln]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 842)

Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENG-NH 2 ;

(SEQ ID NO: 972)

Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH 2 ;

(SEQ ID NO: 752)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QN-[βAla]-NH 2 ;

(SEQ ID NO: 753)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Acbc]-ENN-NH 2 ;

(SEQ ID NO: 754)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Achc]-ENN-NH 2 ;

(SEQ ID NO: 755)

Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Acvc]-ENN-NH 2 ;

(SEQ ID NO: 979)

Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-piperidine]-

ENN-NH 2 ;

(SEQ ID NO: 993)

Ac-[(D)Arg]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-

tetrahydropyran]-ENN-NH 2 ;

or

(SEQ ID NO: 980)

Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-

tetrahydropyran]-ENN-NH 2 ,

wherein the peptide inhibitor comprises a thioether bond between the Abu and the C.

20. The method of claim 19 , wherein the IBD is ulcerative colitis.

21. The method of claim 19 , wherein the IBD is Crohn's disease.

22. The method of claim 19 , wherein the IBD is pouchitis after an ileoanal anastomosis.