a4B7 INTEGRIN THIOETHER PEPTIDE ANTAGONISTS

• US 20160031944A1
• Filed: 05/15/2015
• Published: 02/04/2016
• Est. Priority Date: 05/16/2014
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Zemede, Genet, Mattheakis, Larry C., Frederick, Brian Troy
• Granted Patent: US 9,714,270 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: 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
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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: C07K 14/70546 : Integrin superfamily
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/56 : the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.

Claims

1. A peptide molecule comprising a structure of Formula (V) (SEQ ID NO:

49);

2. The peptide molecule of claim 1, wherein

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methyl-benzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is selected from the group consisting of;

N-Me-Arg, Arg, N-Me-Lys, Phe (4-quanidino), Phe(4-carbamoyl amino), Cit, Phe(4-NH2), N-Me-Homo-Arg, Homo-Arg, Tyr and His;

Xaa⁶ is Ser, Gly, Thr or Ile;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is selected from the group consisting of;

Thr, Val, Ile, Leu, hLeu, Nle, and Val;

Xaa⁹ is selected from the group consisting of;

Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys; and

Xaa¹¹ is absent or selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3), Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe (2-carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is absent or selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-homoGlu, D-Asp, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid, and isosteres;

Xaa¹³ is absent or any amino acid; and

Xaa¹⁴ is any amino acid.

3. The peptide molecule of claim 1, wherein

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser, Gly, Thr, or Ile;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is selected from the group consisting of;

Thr, Val, Ile, Leu, hLeu and Nle;

Xaa⁹ is selected from the group consisting of;

Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3), Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Ser, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and any substituted aromatic amino acid and corresponding D-amino acids;

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu-, corresponding D-amino acid and isosteres;

Xaa¹³ is absent; and

Xaa¹⁴ is any amino acid.

4. The peptide molecule of claim 1, wherein

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser, Gly, Thr, or Ile;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is selected from the group consisting of;

Thr, Val, Ile, Leu, hLeu and Nle;

Xaa⁹ is selected from the group consisting of;

Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser;

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid and isosteres;

Xaa¹³ is absent or any amino acid; and

Xaa¹⁴ is any amino acid.

5. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is selected from the group consisting of;

Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3), Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is absent or selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid and isosteres;

Xaa¹³ is absent; and

Xaa¹⁴ is any amino acid.

6. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is selected from the group consisting of;

Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is absent or selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu;

Xaa¹³ is absent; and

,

Xaa¹⁴ is any amino acid.

7. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid and isosteres;

Xaa¹³ is absent; and

Xaa¹⁴ is any amino acid.

8. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, and beta-homo-Glu;

Xaa¹³ is absent; and

Xaa¹⁴ is any amino acid.

9. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and Ser,

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, and beta-homo-Glu;

Xaa¹³ is absent; and

Xaa¹⁴ is any amino acid.

10. The peptide molecule of claim 1, wherein:

Xaa¹ is absent or any amino acid;

Xaa² is absent or any amino acid;

Xaa³ is absent or any amino acid;

Xaa⁴ is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa¹⁰ or a modified HomoSer, optionally Homo-Ser-Cl;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp or D-Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is Leu;

Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe (4-CH3). Phe (4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, and HomoPhe;

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, and beta-homo-Glu;

Xaa³ is absent; and

Xaa¹⁴ is any amino acid.

11. The peptide molecule of claim 1, wherein Xaa¹, Xaa² and Xaa³ are absent.

12. The peptide molecule of claim 1, wherein Xaa⁴ is a 2-methylbenzoyl moiety.

13. The peptide molecule of claim 1, wherein Xaa⁵ is 2-Me-Arg.

14. The peptide molecule of claim 1, wherein Xaa¹⁴ is selected from the group consisting of:

Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, Homo-Lys, D-Dap, D-Dab, Cys, HomoCys, Pen, or D-Orn.

15. The peptide molecule of claim 1, wherein Xaa⁴ is a 2-methyl benzoyl moiety that forms a thioether bond with Xaa¹⁰, Xaa⁵ is N-Me-Arg, Xaa⁶ is Ser, Xaa⁷ is Asp, Xaa⁸ is Thr, Xaa⁹ is Leu, and Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys.

17. The peptide molecule of claim 1, wherein Xaa¹⁴ is selected from the group consisting of:

D-Lys, N-Me-Lys, and D-N-Me-Lys.

23. The peptide molecule of claim 1, further comprising a terminal modifying group selected from the group consisting of DIG, PEG4, PEG13, PEG25, PEG1K, PEG2K, PEG4K, PEG5K, Polyethylene glycol having molecular weight from 400 Da to 40,000 Da, IDA, Ac-IDA, ADA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, AADA, suitable aliphatic acids, suitable aromatic acids, and heteroaromatic acids.

26. The peptide molecule of claim 1, wherein the peptide molecule is a dimer comprising two peptide molecules of claim 1 dimerized by a linker.

28. The peptide molecule of claim 26, where in the linker is selected from the group consisting of:

DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, Triazine, Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da.

30. A pharmaceutical composition comprising a peptide molecule of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

34. A method for treating or preventing a disease or condition that is associated with a biological function of integrin α

4β

7, the method comprising providing to a subject in need thereof an effective amount of the peptide molecule of claim 1.

35. The method of claim 34, wherein the disease or condition is selected from the group consisting of Inflammatory Bowel Disease (IBD), adult IBD, pediatric IBD, adolescent 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, primary sclerosing cholangitis, human immunodeficiency virus (HIV) infection in the GI tract, eosinophilic asthma, eosinophilic esophagitis, gastritis, colitis, microscopic colitis and graft versus host disease (GVDH).

16. (canceled)

18-19. -19. (canceled)

20. A peptide molecule comprising a structure of Formula (VI) (SEQ ID NO:

387);

21. The peptide molecule of claim 20, wherein Xaa¹ is a 2-methyl benzoyl moiety that forms a thioether bond with Xaa⁷, Xaa² is N-Me-Arg, Xaa³ is Ser, Xaa⁴ is Asp, Xaa⁵ is Thr, Xaa⁶ is Leu, and Xaa⁷ is Pen, Cys, D-Cys or HomoCys.

22. (canceled)

24-25. -25. (canceled)

27. (canceled)

29. (canceled)

31-33. -33. (canceled)

36-46. -46. (canceled)