# US 2014/0193465 A1 · NOVEL a4B7 PEPTIDE DIMER ANTAGONISTS

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- Number: US 2014/0193465 A1
- Document ID: US20140193465A1
- Status: Published application
- Kind: A1
- Application number: 14/050,349
- Filed: 2013-10-10
- Published: 2014-07-10
- Earliest claimed: 2012-10-11
- Assignees: Protagonist Therapeutics, Inc.
- Applicants: Protagonist Therapeutics, Inc.
- Inventors: Ashok Bhandari; Dinesh V. Patel; Larry C. Mattheakis
- Web page: https://patentgrep.com/patent/US20140193465A1

## CPC

- C07K 14/70546: {Integrin superfamily}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/06: having 5 to 11 amino acids
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/47: from mammals
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The invention relates to disulfide-rich dimer molecules which inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, and show high selectivity against α4β1 binding.

## Claims

### Claim 1

A peptide dimer compound comprising two peptide monomer subunits of Formula (I)
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15 (I),
or a pharmaceutically acceptable salt thereof, wherein
Xaa1 is selected from the group consisting of a suitable linker moiety, absent, hydrogen, Ac-, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a corresponding D-amino acid, and a suitable linker moiety;
Xaa2 is selected from the group consisting of Ac-, NH2, a suitable linker moiety, absent, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;
Xaa3 is selected from the group consisting of Ac-, NH2, a suitable linker moiety, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;
Xaa4 is selected from the group consisting of Cys, Pen, Asp, Glu, hGlu, Lys, homo-Lys, Orn, Dap, Dab, a suitable isostere, and a corresponding D-amino acid;
Xaa5 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, homo-Arg, Dap, Dab, N-Me-Arg, Arg-(Me)sym, Arg-(me)asym, 4-Guan, Cit, Cav, a suitable isostere, and a corresponding D-amino acid;
Xaa6 is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, a suitable isostere replacement and a corresponding D-amino acid;
Xaa7 is selected from the group consisting of Asp, N-Me-Asp, a suitable isostere replacement for Asp, and a corresponding D-amino acid;
Xaa8 is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tye, Trp, Met, an N-Methyl amino acid; a suitable isostere, and a corresponding D-amino acid;
Xaa9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Asn, Glu, Val, homo-Leu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, N-Me-Leu, a suitable isostere, and a corresponding D-amino acid;
Xaa10 is selected from the group consisting of Cys, Asp, Pen, Lys, homo-Lys, Orn, GluDap, Dab, a suitable isostere, and a corresponding D-amino acid;
Xaa11 is selected from the group consisting of Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, CONH2, His, Glu, Ser, Arg, Pro, Phe, Sar, 1Nal, 2Nal, hPhe, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, an aromatic ring substituted Phe, an aromatic ring substituted Trp, an aromatic ring substituted His, a hetero aromatic amino acid, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, a corresponding D-amino acid; a suitable isostere; and a suitable linker moiety.
Xaa12 is selected from the group consisting of Glu, Amide, Lys, COOH, CONH2, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;
Xaa13 is selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, COOH, CONH2, NH2, absent, a suitable linker moiety, a suitable isostere, and a corresponding D-amino acid;
Xaa14 is selected from the group consisting of a natural amino acid, absent, COOH, CONH2, NH2, a suitable isostere, a suitable linker, a corresponding D-amino acid, and an N-Methyl amino acid; and
Xaa15 is selected from the group consisting of a suitable linker, and absent.

### Claim 2 (depends on 1)

The peptide dimer compound of claim 1, wherein when Xaa1 is absent, Xaa2 is selected from the group consisting of Ac, NH2 and a suitable linker.

### Claim 3 (depends on 1)

The peptide dimer compound of claim 1, wherein when Xaa1 and Xaa2 are absent, Xaa3 is selected from the group consisting of Ac, NH2 and a suitable linker.

### Claim 4 (depends on 1)

The peptide dimer compound of claim 1, wherein when Xaa10 is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, Xaa4 is selected from the group consisting of Asp, Glu, and hGlu, and when Xaa10 is selected from the group consisting of Asp, Glu, and hGlu, Xaa4 is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab.

### Claim 5 (depends on 1)

The peptide dimer compound of claim 1, wherein when Xaa4 and Xaa10 are selected from the group consisting of Cys and Pen, Xaa4 and Xaa10 are cyclized through a disulfide bond.

### Claim 6 (depends on 1)

The peptide dimer compound of claim 1, wherein when Xaa4 is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, and when Xaa10 is selected from the group consisting of Asp, Glu, and hGlu, Xaa4 and Xaa10 are cyclized through an amide bond.

### Claim 7 (depends on 1)

The peptide dimer compound of claim 1, wherein the suitable linker is selected from the group consisting of DIG, DIG-OH, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, suitable aromatics, heteroaromatics, and polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da.

### Claim 8 (depends on 1)

A method for treating inflammatory bowel disease in a patient, comprising administering to the patient an effective amount of a peptide dimer compound of claim 1.

### Claim 9 (depends on 8)

The method of claim 8, wherein the inflammatory bowel disease is ulcerative colitis.

### Claim 10 (depends on 8)

The method of claim 8, wherein the inflammatory bowel disease is Crohn's disease.

### Claim 11 (depends on 8)

The method of claim 8, wherein the peptide dimer compound inhibits binding of α4β7 to MAdCAM.

### Claim 12 (depends on 1)

A method for treating a human having an inflammatory bowel disease, comprising the steps of administering to the human an effective amount of a peptide dimer according to the composition of claim 1.

### Claim 13 (depends on 12)

The method of claim 12, further comprising a step wherein the peptide dimer is administered as an initial does followed by one or more subsequent doses and the minimum interval between any two doses is a period of less than 1 day, and wherein each of the doses comprises an effective amount of the peptide dimer.

### Claim 14 (depends on 12)

The method of claim 12, wherein the effective amount of peptide dimer is sufficient to achieve at least one of the following selected from the group consisting of: a) about 50% or greater saturation of MAdCAM binding sites on α4β7 integrin molecules; b) about 50% or greater inhibition of α4β7 integrin expression on the cell surface; and c) about 50% or greater saturation of MAdCAM binding sites on α4β7 molecules and about 50% or greater inhibition of α4β7 integrin expression on the cell surface, wherein i) the saturation is maintained for a period consistent with a dosing frequency of no more than twice daily; ii) the inhibition is maintained for a period consistent with a dosing frequency of no more than twice daily; or iii) the saturation and the inhibition are each maintained for a period consistent with a dosing frequency of no more than twice daily;

### Claim 15 (depends on 12)

The method of claim 12, wherein the peptide dimer is administered orally.

### Claim 16 (depends on 12)

The method of claim 12, wherein the peptide dimer is administered parenterally.

### Claim 17 (depends on 12)

The method of claim 12, wherein the peptide dimer is administered topically.

### Claim 18 (depends on 12)

The method of claim 12, wherein the peptide dimer is selected from the group consisting of SEQ ID NO: 39-136.

### Claim 19 (depends on 12)

The method of claim 12, further comprising a step for administering the peptide dimer to the human at an interval sufficient to ameliorate the inflammatory bowel disease.

### Claim 20 (depends on 1)

A method for treating a human afflicted with a condition that is associated with a biological function of α4β7, the method comprising administering to the human a peptide dimer according to the composition of claim 1.

### Claim 21 (depends on 20)

The method of claim 20, further comprising a step for administering the peptide dimer to the human at an interval sufficient to ameliorate the condition.

### Claim 22 (depends on 21)

The method of claim 21, wherein the interval is selected from the group consisting of around the clock, hourly, every four hours, once daily, twice daily, three times daily, four times daily, every other day, weekly, bi-weekly, and monthly.

### Claim 23 (depends on 1)

A method for stabilizing a peptide dimer compound according to claim 1, the method comprising a step for substituting Xaa4 and Xaa10 with an amino acid residue selected from the group consisting of Cys and Pen, wherein Xaa4 and Xaa10 form a cyclized structure through a disulfide bond.

### Claim 24

A method for stabilizing a peptide dimer compound of Formula (II)
Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12 (II),
or a pharmaceutically acceptable salt thereof, wherein the method comprises a step for substituting Xaa4 and Xaa10 with compatible amino acid residues that are capable of forming a cyclized structure through at least one of an amide bond and a disulfide bond.

### Claim 25 (depends on 23)

The method of claim 23, wherein the compatible amino acids are selected from the group consisting of Cys and Pen, wherein Xaa4 and Xaa10 form a cyclized structure through a disulfide bond.

### Claim 26 (depends on 24)

The method of claim 24, wherein when Xaa4 is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, and when Xaa10 is selected from the group consisting of Asp, Glu, hGlu, β-Asp, and β-Glu, Xaa4 and Xaa10 are cyclized through an amide bond.

### Claim 27

A pharmaceutical composition comprising a peptide dimer compound according to at least one of Formula (I) and Formula (II).

### Claim 28 (depends on 27)

The composition of claim 27, further comprising an enteric coating.

### Claim 29 (depends on 28)

The composition of claim 28, wherein the enteric coating protects and releases the pharmaceutical composition with a subjects lower gastrointestinal system.

### Claim 30 (depends on 27)

A method for treating a condition in a subject comprising administering the pharmaceutical composition of claim 27 to the subject, wherein the condition is treatable by reducing the activity (partially or fully) of α4β7 in the subject.

### Claim 31 (depends on 30)

The method of claim 30, wherein the subject is a human being.

### Claim 32 (depends on 30)

The method of claim 30, wherein the condition is an inflammatory condition of the gastrointestinal system.

### Claim 33

A method for treating a human afflicted with a condition that is associated with a biological function α4β7 and comprising administering to the individual a peptide dimer of Formula (I) in an amount sufficient to inhibit (partially or fully) the biological function of α4β7 to tissues expressing MAdCAM.

### Claim 34

A method for treating a human afflicted with a condition that is associated with a biological function of α4β7 and comprising administering to the individual a peptide dimer of Formula (I) in an effective amount sufficient to at least partially inhibit the biological function of α4β7 to tissues expressing MAdCAM.

### Claim 35 (depends on 33)

The method of claim 33, wherein the condition is inflammatory bowel disease.

### Claim 36 (depends on 32)

The method of claim 32, wherein the condition is selected from the group consisting of Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiotherapy, chemotherapy, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, and graft versus host disease.

### Claim 37 (depends on 33)

The method of claim 33, wherein the peptide dimer is administered to the individual by a form of administration selected from the group consisting of oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, vaginal, and topical.

### Claim 38

A method for treating an individual with an α4β7 integrin antagonist dimer molecule according to at least one of Formula (I) and Formula (II), wherein the α4β7 integrin antagonist dimer molecule comprises an increased half-life.

### Claim 39 (depends on 37)

The method of claim 37, wherein the increased half-life is at least one day in vitro or in vivo.

### Claim 40 (depends on 36)

The method of claim 36, wherein when the half-life is equal to or greater than a period consistent with no more frequent than twice daily dosing in vivo, the α4β7 integrin antagonist dimer molecule comprises a pharmaceutical preparation that is administered orally.

### Claim 41 (depends on 36)

The method of claim 36, wherein when the half-life is from approximately 12 hours to greater than 24 in vivo, the α4β7 integrin antagonist dimer molecule comprises a pharmaceutical preparation that is administered parenterally.

### Claim 42 (depends on 36)

The method of claim 36, wherein when the half-life is from approximately 12 hours to greater than 24 hours in vivo, the α4β7 integrin antagonist dimer molecule comprises a pharmaceutical preparation that is administered topically