IL-23 RECEPTOR ANTAGONISTS AND USES THEREOF

• US 20100190710A1
• Filed: 07/07/2008
• Published: 07/29/2010
• Est. Priority Date: 07/06/2007
• Status: Abandoned Application

• Current Assignee: Valorisation HSJ
• Original Assignee: Valorisation HSJ
• Inventors: Chemtob, Sylvain, Quiniou, Christiane, Lubell, William D.
• Application Number:
  US12/666,028
• Publication Number:
  US 20100190710A1
• Time in Patent Office: Days
• US Class Current: 514/1.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 14/4703 : Inhibitors; Suppressors
• CPC Class Codes: C07K 14/4705 : stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/5434 : IL-12
• CPC Class Codes: C07K 14/7155 : for interleukins [IL]
• CPC Class Codes: G01N 33/6869 : Interleukin

Abstract

The present invention relates to IL-23 receptor antagonists and agonists. The use of IL-23 receptor antagonists in treating autoimmune and inflammatory disorders, as well as methods of identifying IL-23 receptor antagonists and agonists.

Claims

1. A compound comprising a sequence characterized by the formula T₁E₂E₃E₄Q₅Q₆Y₇L₈, wherein said compound is 25 or fewer amino acids in length, wherein said compound antagonizes a biological activity of an interleukin 23 (IL-23) receptor, and wherein;

T₁ is selected from the group consisting of no residue, threonine, phenylalanine, alanine, and Σ

, where Σ

defines an alpha-amino acid comprising a hydrophobic side-chain Σ

or aromatic side chain;

E₂, E₃, and E₄ each independently is selected from the group consisting of no residue, alanine, glutamic acid, glutamine, aspartic acid, asparagine, serine, histidine, homoserine, beta-leucine, beta-phenylalanine, alpha amino adipic acid, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine;

Q₅ and Q₆ each independently is selected from the group consisting of no residue, alanine, glutamine, aspartic acid, asparagine, glutamic acid, serine, homoserine, alpha-amino adipic acid, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine;

Y₇ is selected from the group consisting of no residue, tyrosine, phenylalanine, tryptophan, alanine, histidine, pyridylalanine, and Σ

where Σ

is an alpha-amino acid comprising a hydrophobic side-chain Σ

or aromatic side chain or heteroaromatic side chain; and

L₈ is selected from the group consisting of no residue, leucine, alanine, valine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine.

2. The compound of claim 1, wherein said compound comprises at least one D-amino acid.

3. The compound of claim 1, wherein said alpha-amino acid comprising a hydrophobic side-chain is nor-leucine, iso-leucine, tert-leucine, cyclohexylalanine, or allylglycine.

4. The compound of claim 1, wherein said aliphatic amine of one to ten carbons is a methylamine, iso-butylamine, iso-valerylamine, cyclopentylamine, cyclohexylmethylamine, or cyclohexylamine.

11. The compound of claim 1, wherein said compound consists of the sequence TEEEQQYL (SEQ ID NO:

1), TAAEQQYL (SEQ ID NO;

7), TAAAQQYL (SEQ ID NO;

8), EEEQQYL (SEQ ID NO;

9), AEEQQYL (SEQ ID NO;

12), TEEEQ (SEQ ID NO;

15), TEEE (SEQ ID NO;

16), TEEEQAYL (SEQ ID NO;

17), or TEEEAAYL (SEQ ID NO;

18).

12. The compound of claim 11, wherein at least one amino acid is a D-amino acid.

67. A cell expressing the compound of claim 1.

70. A pharmaceutical composition comprising the compound of claim 1.

71. A method of treating an autoimmune or inflammatory disorder, said method comprising administering to a subject in need thereof an effective dose of the compound of claim 1.

75. A method of identifying a candidate compound that inhibits or enhances the ability of the compound of claim 1 to antagonize a biological activity of an interleukin 23 receptor, said method comprising:

(i) contacting the interleukin 23 receptor with the candidate compound in the presence of the compound of claim 1; and

(ii) assaying for an increase or decrease of the biological activity of the interleukin 23 receptor relative to a control not contacted with the candidate compound, wherein a decrease of said biological activity relative to said control indicates that said candidate compound enhances the ability of the compound of claim 1 to antagonize a biological activity of an interleukin 23 receptor, and wherein an increase of said biological activity relative to said control indicates that said candidate compound inhibits the ability of the compound of claim 1 to antagonize a biological activity of an interleukin 23 receptor.

5-10. -10. (canceled)

13-17. -17. (canceled)

18. A compound comprising a sequence characterized by the formula M₁E₂E₃S₄K₅Q₆L₇Q₈L₉, wherein said compound is 25 or fewer amino acids in length, wherein said compound antagonizes a biological activity of an interleukin 23 (IL-23) receptor, and wherein;

M₁ is selected from the group consisting of no residue, methionine, valine, leucine, alanine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

E₂ and E₃ each independently is selected from the group consisting of no residue, alanine, glutamic acid, glutamine, aspartic acid, asparagine, serine, histidine, homoserine, beta-leucine, beta-phenylalanine, alpha amino adipic acid, trimesic acid, or an alpha,omega-dicarboxylic acid (e.g., succinic acid, glutaric acid, or azelic acid), and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine;

S₄ is selected from the group consisting of no residue, serine, threonine, allothreonine, hydroxyproline, beta-hydroxyvaline, valine, and η

, where η

is a neutral hydrophilic amino acid;

K₅ is selected from the group consisting of no residue, glutamine, lysine, arginine, histidine, alanine, ornithine, citruline, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, and an arginine surrogate;

Q₆ is selected from the group consisting of no residue, alanine, glutamine, aspartic acid, asparagine, glutamic acid, serine, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine;

L₇ is selected from the group consisting of no residue, leucine, alanine, valine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine;

Q₈ is selected from the group consisting of no residue, glutamine, aspartic acid, asparagine, glutamic acid, serine, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine; and

L₉ is selected from the group consisting of no residue, leucine, isoleucine, alanine, valine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine.

19. The compound of claim 18, wherein said compound comprises at least one D-amino acid.

27. The compound of claim 18, wherein said compound consists of the sequence MEESKQLQL (SEQ ID NO:

2), MAESKQLQL (SEQ ID NO;

19), MAASKQLQL (SEQ ID NO;

20), ESKQLQL (SEQ ID NO;

21), MEESKQLQI (SEQ ID NO;

22), MEESKQL (SEQ ID NO;

23), MEESKQ (SEQ ID NO;

24), MEESQQLQI (SEQ ID NO;

25), EESKQLQL (SEQ ID NO;

26), VQAANALGMEESKQLQLHLDDLVL (SEQ ID NO;

27), or LVLDDLHLQLQKSEEMGLANAAQV (SEQ ID NO;

28).

28. The compound of claim 27, wherein at least one amino acid is a D-amino acid.

20-26. -26. (canceled)

29-32. -32. (canceled)

33. A compound comprising a sequence characterized by the formula K₁K₂Y₃L₄V₅W₆V₇Q₈, wherein said compound is 25 or fewer amino acid in length, wherein said compound antagonizes a biological activity of an interleukin 23 (IL-23) receptor, and wherein;

K₁ and K₂ each independently is selected from the group consisting of no residue, lysine, arginine, histidine, alanine, ornithine, citruline, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, and an arginine surrogate;

Y₃ is selected from the group consisting of no residue, tyrosine, phenylalanine, tryptophan, alanine, and Σ

where Σ

is an alpha-amino acid comprising a hydrophobic side-chain Σ

or aromatic side chain, or heteroaromatic side chain;

L₄ is selected from the group consisting of no residue, leucine, alanine, valine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine;

V₅ is selected from the group consisting of no residue, valine, leucine, alanine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine;

W₆ is selected from the group consisting of no residue, tryptophan, tyrosine, phenylalanine, alanine, and Σ

where Σ

is an alpha-amino acid comprising a hydrophobic side-chain Σ

or aromatic side chain;

or heteroaromatic side chain;

V₇ is selected from the group consisting of no residue, valine, leucine, alanine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine; and

Q₈ is selected from the group consisting of no residue, glutamine, aspartic acid, asparagine, glutamic acid, serine, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine.

34. The compound of claim 33, wherein said compound comprises at least one D-amino acid.

35-47. -47. (canceled)

48. A compound comprising a sequence characterized by the formula L₁P₂D₃E₄V₅T₆C₇V₈, wherein said compound is 25 or fewer amino acids in length, wherein said compound antagonizes a biological activity of an interleukin 23 (IL-23) receptor, and wherein;

L₁ is selected from the group consisting of no residue, leucine, alanine, valine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

P₂ is selected from the group consisting of no residue, proline, alanine, N-methylglycine, N-isobutylglycine, aminoisobutyric acid (Aib), N-Methyl-L-alanine (MeAla), trans-4-Hydroxyproline, diethylthiazolidine carboxylic acid (Dtc), and Ω

, where Ω

is a conformational constraint-producing amino acid;

D₃ is selected from the group consisting of no residue, aspartic acid, asparagine, glutamic acid, glutamine, serine, histidine, homoserine, beta-leucine, beta-phenylalanine, alpha amino adipic acid, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine, or a primary arylalkyl amine;

E₄ is selected from the group consisting of no residue, alanine, glutamic acid, glutamine, aspartic acid, asparagine, serine, histidine, homoserine, beta-leucine, beta-phenylalanine, alpha amino adipic acid, and Ψ

where Ψ

is a 3-amino-5-phenylpentanoic acid-alpha-amino acid comprising a hydrophobic side-chain, an aromatic amine, an aliphatic amine or a primary arylalkyl amine;

V₅ is selected from the group consisting of no residue, valine, leucine, alanine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine;

or a heteroaromatic or heteroarylalkylamine;

T₆ is selected from the group consisting of no residue, threonine, phenylalanine, alanine, and Σ

where Σ

defines an alpha-amino acid comprising a hydrophobic side-chain Σ

or aromatic side chain;

C₇ is selected from the group consisting of no residue, cysteine, serine, homoserine, homocysteine, threonine, methionine, N-acetylcysteine, cystathionine, 2-aminobutyrate, and β

,β

-dimethylcysteine (Penicillamine); and

V₈ is selected from the group consisting of no residue, valine, leucine, alanine, methionine, phenylalanine, tryptophan, and φ

where φ

is an alpha-amino acid comprising a hydrophobic side-chain;

an aliphatic amine of one to ten carbons;

or an aromatic or arylalkylamine.

49. The compound of claim 48 wherein said compound comprises at least one D-amino acid.

50-62. -62. (canceled)

63. A vector comprising an isolated nucleic acid sequence encoding the amino acid sequence of any one of SEQ ID NOS:

1-5.

64. A cell comprising the vector of claim 63.

65-66. -66. (canceled)

68-69. -69. (canceled)

72-74. -74. (canceled)

76-79. -79. (canceled)