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

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)

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.

6. The peptide inhibitor 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.

7. The peptide inhibitor of claim 6 , 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.

8. The peptide inhibitor of claim 6 , 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 α-Me-Lys, α-Me-Leu, α-Me-Ser, α-Me-Val, Achc, Acvc, Acpc, Acbc or 4-amino-4-carboxy-tetrahydropyran.

9. The peptide inhibitor of claim 8 , 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: 438)

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

[α-MeLys]-E-N-G;

(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]-QTWQQ]]-[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-NH3;

(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.

10. The peptide inhibitor of claim 1 , wherein the peptide inhibitor comprises the structure of Formula I:

R 1 -X—R 2   (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein

R 1 is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl, a C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence; and

R 2 is OH or NH 2.

11. 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 Xa:

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

wherein

X1 is any amino acid or absent;

X2 is any amino acid or absent;

X3 is any amino acid or absent;

X4 is Pen, Cys or homo-Cys;

X5 is any amino acid;

X6 is any amino acid;

X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl 2 ), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-Me-Trp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO 2 H), Phe(4-CONH 2 ), Phe(3,4-Dimethoxy), Phe(4-CF 3 ), Phe(4-tBu), ββ-diPheAla, 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 Pen, Cys or hCys;

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, 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 ), 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-OMe 2 ) 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 α-MeLys, α-MeOrn, α-MeLeu, α-MeVal, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, 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, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, 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, Lys(Ac), Orn 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, Asn, Ser, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, Arg 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 comprises a disulfide bond between X4 and X9.

12. The peptide inhibitor of claim 11 , wherein both X4 and X9 are Pen.

13. The peptide inhibitor of claim 11 , wherein X18 is (D)-Lys.

14. The peptide inhibitor of claim 11 , comprising one or more, two or more, three or more, or four of the following:

X5 is Arg, Asn, Gln, Dap, Orn;

X6 is Thr or Ser;

and

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

15. The peptide inhibitor of claim 11 , comprising 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(Bzl) or Phe(4-Me), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norharman;

X12 is Arg, α-MeLys α-MeLeu, Aib or α-MeOrn;

X13 is Lys, Glu or Lys(Ac);

X14 is Phe or Asn;

X15 is Asn, Gly, Ser, or βAla; and

X16 is absent.

16. The peptide inhibitor of claim 15 , wherein X4 and X9 are Pen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Tyr or a Phe analog; X11 is Trp, 2-Nal or 1-Nal; X12 is Arg, αMeLys or α-MeOrn; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly; and X16 is absent.

17. The peptide inhibitor of claim 11 , wherein the Phe analog is Phe(3,4-F 2 ), Phe(3,4-Cl 2 ), Phe(3-Me), Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH 2 ), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH 2 ), Phe(4-N 3 ), Phe(4-OMe), or Phe(4-OBzl).

18. The peptide inhibitor of claim 15 , 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).

19. 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 Xa:

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

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-Cl 2 ), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO 2 H), Phe(4-CONH 2 ), Phe(3,4-Dimethoxy), Phe(4-CF 3 ), ββ-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, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl 2 ), Phe(3,4-F 2 ), βhPhe(4-F), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO 2 H), Phe(4-CONH 2 ), Phe(3,4-Dimethoxy), Phe(4-CF 3 ), Phe(2,3-Cl 2 ), Phe(2,3-F 2 ), Phe(4-F), 4-phenylcyclohexylalanine, α-MePhe, βhPhe, βhTyr, βhTrp, 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), Phe(4-OBzl), or Octgly, or a corresponding α-methyl amino acid form of any of the foregoing;

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, βhGlu, βhAla, βhLeu, βhVal, 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, βAla, βhGlu, βhAla, βhLeu, βhVal, 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; and

X17 is absent, Glu, Ser, Gly or Gln, or a corresponding α-methyl amino acid form of any of the foregoing,

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

20. The peptide inhibitor of claim 19 , wherein X4 or X9 is Abu.

21. The peptide inhibitor of claim 19 , comprising 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.

22. The peptide inhibitor of claim 19 , comprising 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.

23. The peptide inhibitor of claim 22 , 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-guanadino).

24. A pharmaceutical composition comprising the peptide inhibitor of any one of claims 1 , 2 - 5 , 6 - 11 , 12 - 16 , 19 or 10 - 20 , and a pharmaceutically acceptable carrier, excipient, or diluent.