ORAL PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR AND THEIR USE TO TREAT INFLAMMATORY BOWEL DISEASES
First Claim
Patent Images
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)whereinX1 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-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-Cl2), Phe(4-CF3), Bip, Cha, 4-PyridylAlanine, β
hTyr, OctGly, Phe(4-N3), 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-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
hNal, β
hPhe, β
hTyr, β
hTrp, 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-CONH2), Phe(3,4-Dimethoxy), Phe(2,3-Cl2), Phe(2,3-F2), 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, 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 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, β
hAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α
-MeLeu, Aib, β
-Ala, 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)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, andwherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.
1 Assignment
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Accused Products
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.
26 Citations
49 Claims
-
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-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-Cl2), Phe(4-CF3), Bip, Cha, 4-PyridylAlanine, β
hTyr, OctGly, Phe(4-N3), 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-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
hNal, β
hPhe, β
hTyr, β
hTrp, 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-CONH2), Phe(3,4-Dimethoxy), Phe(2,3-Cl2), Phe(2,3-F2), 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, 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 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, β
hAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α
-MeLeu, Aib, β
-Ala, 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)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. - View Dependent Claims (7, 9, 10, 11, 13, 14, 15, 16, 35, 44, 47, 48)
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:
-
13. 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.
-
-
14. The peptide inhibitor of claim 13, 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.
- or
-
15. The peptide inhibitor of claim 13, 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.
-
-
16. The peptide inhibitor of claim 15, wherein the peptide inhibitor comprises any of the following amino acid sequences:
-
Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α
-MeLys]-E-N-G (SEQ ID NO;
430);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α
-MeOrn]-ENG-NH2 (SEQ ID NO;
431);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CO2H)]-[2-Nal]-[α
-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO;
432);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α
-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO;
433);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CONH2)]-[2-Nal]-[α
-MeLys]-[Lys(Ac)]NG-NH2 (SEQ ID NO;
434);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α
-MeLys]-[Lys(Ac)]-NA-NH2 (SEQ ID NO;
435);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α
-MeLys]-[Lys(Ac)]-NAE-NH2 (SEQ ID NO;
436);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α
-MeLys]-ENG-NH2 (SEQ ID NO;
437);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-(2-aminoethoxy))]-W-[α
-MeLys]-E-N-G (SEQ ID NO;
438);Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α
-MeLys]-DNG-NH2 (SEQ ID NO;
439);
-
-
35. The peptide inhibitor of claim 1, wherein the peptide inhibitor comprises the structure of Formula I:
-
R1—
X—
R2
(I)or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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; andR2 is OH or NH2.
-
-
44. A pharmaceutical composition comprising the peptide inhibitor of any one of claims 1-35 or the peptide dimer inhibitor of claim 36, and a pharmaceutically acceptable carrier, excipient, or diluent.
-
47. A method for treating an Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn'"'"'s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease in a subject, comprising providing to the subject an effective amount of the pharmaceutical composition of claim 44.
-
48. The method of claim 47, wherein the pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topically, vaginal, or topical route of administration.
-
2-6. -6. (canceled)
-
8. (canceled)
-
12. (canceled)
-
17. A peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, where the peptide inhibitor comprises an 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; The, 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-Cl2), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α
-Me-Trp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO2H), Phe(4-CONH2), Phe(3,4-Dimethoxy), Phe(4-CF3), Phe(4-tBu), β
β
-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 (optionally, Phe(3,4-F2), Phe(3,4-Cl2), F(3-Me), Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH2), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH2), Phe(4-N3), Phe(4-OMe), or Phe(4-OBzl)), 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), α
-MePhe, β
hNal, β
hPhe, β
hTyr, β
hTrp, 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-CONH2), Phe(3,4-OMe2) Phe(2,3-Cl2), Phe(2,3-F2), 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, 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, 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. - View Dependent Claims (22, 23, 24, 25, 26)
-
-
18-21. -21. (canceled)
-
27. (canceled)
-
28. 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 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-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, Tic, 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), 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, Acpc, 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, 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; andX17 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. - View Dependent Claims (32, 33, 34)
-
-
29-31. -31. (canceled)
-
36-43. -43. (canceled)
-
45-46. -46. (canceled)
-
49-54. -54. (canceled)
Specification