ORAL PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR AND THEIR USE TO TREAT INFLAMMATORY BOWEL DISEASES
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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.
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Citations
77 Claims
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1-46. -46. (canceled)
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47. 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):
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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, 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-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-Cl), Phe(4-CF3), Bip, Cha, 4-PyridylAlanine, β
hTyr, OctGly, Phe(4-N3), 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-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
hPhe, β
hTyr, β
hTrp, 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-CONH2), Phe(3,4-Dimethoxy), Phe(2,3-Cl2), Phe(2,3-F2), 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, β
-Aib, 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, 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, β
hAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α
-MeLeu, Aib, 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)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. - View Dependent Claims (48, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 71)
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49-55. -55. (canceled)
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69. 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 the amino acid sequence of Formula IIIa:
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X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(IIIa)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, 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), or Phe(4-OBzl);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, 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, (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;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 is cyclized via an intramolecular bond between X4 and X9. - View Dependent Claims (70, 72, 73, 74, 75, 76, 77)
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Specification