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),or a pharmaceutically acceptable salt thereof,whereinX1 is any amino acid or absent;
X2 is any amino acid or absent;
X3 is any amino acid or absent;
X4 is Abu;
X5 is Gln;
X6 is Thr;
X7 is Trp;
X8 is Gln;
X9 is Cys;
X10 is Phe, Tyr, a Phe analog, or a Tyr analog;
X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl2);
X12 is α
-Me-Lys, α
-Me-Leu, α
-Me-Ser, α
-Me-Val, Achc, Acvc, Acpc, Acbc, Aib, or 4-amino-4-carboxy-tetrahydropyran;
X13 is any amino acid;
X14 is any amino acid;
X15 is any amino acid,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 thioether bond between X4 and X9, andwherein 1-Nal is L-1-napthylalanine, 2-Nal is L-2-napthylalanine, Abu is 2-aminobutyric acid, α
-Me-Lys is alpha-methyl-L-Lysine, α
-Me-Leu is alpha-methyl-L-Leucine, α
-Me-Ser is alpha-methyl-L-Serine, α
-Me-Val is alpha-methyl-L-Valine, Ache is 1-aminocyclohexanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, and Aib is 2-aminoisobutyric acid.
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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.
18 Citations
30 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),or a pharmaceutically acceptable salt thereof, 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; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X9 is Cys; X10 is Phe, Tyr, a Phe analog, or a Tyr analog; X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), or Phe(3,4-Cl2); X12 is α
-Me-Lys, α
-Me-Leu, α
-Me-Ser, α
-Me-Val, Achc, Acvc, Acpc, Acbc, Aib, or 4-amino-4-carboxy-tetrahydropyran;X13 is any amino acid; X14 is any amino acid; X15 is any amino acid, 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 thioether bond between X4 and X9, and wherein 1-Nal is L-1-napthylalanine, 2-Nal is L-2-napthylalanine, Abu is 2-aminobutyric acid, α
-Me-Lys is alpha-methyl-L-Lysine, α
-Me-Leu is alpha-methyl-L-Leucine, α
-Me-Ser is alpha-methyl-L-Serine, α
-Me-Val is alpha-methyl-L-Valine, Ache is 1-aminocyclohexanecarboxylic acid, Acvc is 1-aminocyclopentanecarboxylic acid, Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, and Aib is 2-aminoisobutyric acid. - 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, 27, 28, 29, 30)
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Specification