ORAL PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR AND THEIR USE TO TREAT INFLAMMATORY BOWEL DISEASES
First Claim
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1. A peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence consisting of Formula (Xa):
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X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Xa)whereinX1 is absent;
X2 is absent;
X3 is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, or absent;
X4 is Pen;
X5 is Dap, Dap(Ac), Gly, Lys, Gln, Arg, Ser, Thr, or Asn;
X6 is Thr;
X7 is Trp;
X8 is Gln;
X9 is Pen;
X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog;
X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl2);
X12 is Acpc, Acbc, Acvc, Achc, Aib, α
-DiethylGly, α
-MeLys, α
-MeLys(Ac), α
-MeLeu, α
-MeOrn, α
-MeSer, α
-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg, or 4-amino-4-carboxy-tetrahydropyran;
X13 is Cit, Asp, Glu, Lys, Lys(Ac), Asn, or Gln;
X14 is Dab(Ac), Dap(Ac), His, Lys(Ac), Asn, Gln, or Tyr;
X15 is Ala, betaAla, Gly, Asn, Gln, or Ser;
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 disulfide bond between X4 and X9 of the amino acid sequence, andwherein 2-Nal is L-2-Napthylalanine, Pen is L-Penicillamine, Dap is L-Diaminopropionic acid, Dap(Ac) is L-Diaminopropionic acid(Ac), 1-Nal is L-1-Napthylalanine,Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Achc is 1-aminocyclohexanecarboxylic acid, Aib is 2-aminoisobutyric acid, α
-MeLys is alpha-methyl-L-Lysine, α
-MeLys(Ac) is alpha-methyl-L-Lysine(Ac), α
-MeLeu is alpha-methyl-L-Leucine, α
-MeOrn is alpha-methyl-L-Ornathine, α
-MeSer is alpha-methyl-L-Serine, α
-MeVal is alpha-methyl-L-Valine, Cha is Cyclohexyl-L-alanine, Cit is L-Citrulline, hLeu is L-homoLeucine, Dab(Ac) is L-Diaminobutyric acid(Ac), betaAla is Beta-alanine, and Dap(Ac) is L-Diaminopropionic acid(Ac).
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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
26 Claims
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1. A peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence consisting of Formula (Xa):
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X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Xa)wherein X1 is absent; X2 is absent; X3 is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, or absent; X4 is Pen; X5 is Dap, Dap(Ac), Gly, Lys, Gln, Arg, Ser, Thr, or Asn; X6 is Thr; X7 is Trp; X8 is Gln; X9 is Pen; X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog; X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl2); X12 is Acpc, Acbc, Acvc, Achc, Aib, α
-DiethylGly, α
-MeLys, α
-MeLys(Ac), α
-MeLeu, α
-MeOrn, α
-MeSer, α
-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg, or 4-amino-4-carboxy-tetrahydropyran;X13 is Cit, Asp, Glu, Lys, Lys(Ac), Asn, or Gln; X14 is Dab(Ac), Dap(Ac), His, Lys(Ac), Asn, Gln, or Tyr; X15 is Ala, betaAla, Gly, Asn, Gln, or Ser; 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 disulfide bond between X4 and X9 of the amino acid sequence, and wherein 2-Nal is L-2-Napthylalanine, Pen is L-Penicillamine, Dap is L-Diaminopropionic acid, Dap(Ac) is L-Diaminopropionic acid(Ac), 1-Nal is L-1-Napthylalanine, Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Achc is 1-aminocyclohexanecarboxylic acid, Aib is 2-aminoisobutyric acid, α
-MeLys is alpha-methyl-L-Lysine, α
-MeLys(Ac) is alpha-methyl-L-Lysine(Ac), α
-MeLeu is alpha-methyl-L-Leucine, α
-MeOrn is alpha-methyl-L-Ornathine, α
-MeSer is alpha-methyl-L-Serine, α
-MeVal is alpha-methyl-L-Valine, Cha is Cyclohexyl-L-alanine, Cit is L-Citrulline, hLeu is L-homoLeucine, Dab(Ac) is L-Diaminobutyric acid(Ac), betaAla is Beta-alanine, and Dap(Ac) is L-Diaminopropionic acid(Ac). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
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Specification