# US 10,370,425 B2 · Peptide antagonists of the calcitonin CGRP family of peptide hormones and their use

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- Number: US 10,370,425 B2
- Document ID: US10370425B2
- Status: Granted
- Kind: B2
- Application number: 15/478,053
- Filed: 2017-04-03
- Published: 2017-07-20
- Granted: 2019-08-06
- Earliest claimed: 2012-01-26
- Applicants: Christopher Joseph Soares
- Inventors: Christopher Joseph Soares
- Web page: https://patentgrep.com/patent/US10370425B2

## CPC

- C07K 14/57527: {Calcitonin gene related peptide}
- A61K 38/225: {Calcitonin gene related peptide}
- A61K 38/23: Calcitonins
- A61P 5/18: of the parathyroid hormones
- A61P 5/22: for decreasing, blocking or antagonising the activity of calcitonin
- A61P 25/06: Antimigraine agents
- C07K 14/585: Calcitonins
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The embodiments provide a modified calcitonin gene-related peptide antagonist including an N-terminal fragment of modified calcitonin gene-related peptide or related protein family member where at least two residues of the N-terminal fragment are cysteine (Cys) and at least one amino acid comprises a non-threonine substitution of a threonine (Thr) residue; a central core where the central core comprises an a-helix; and a C-terminal fragment of modified calcitonin gene-related peptide or related protein family member comprising a C-terminal amide and where at least one amino acid of the C-terminal fragment is phenylalanine (Phe), proline (Pro), tyrosine (Tyr) or hydroxyproline (Hyp) or pharmaceutically acceptable salt thereof, as well as compositions, including pharmaceutical compositions, comprising a subject peptide. The embodiments further provide treatment methods, including methods of treating a migraine, the methods generally involving administering to an individual in need thereof an effective amount of a subject peptide or composition.

## Claims

### Claim 1

A calcitonin gene-related peptide antagonist, or a pharmaceutically acceptable salt thereof, said antagonist having the structure of Formula I:
X1—Y1—Z1 (I)
wherein:
X1 is a modified N-terminal fragment of calcitonin gene-related peptide comprising from five to seven amino acid residues, wherein exactly two amino acids of the N-terminal fragment are cysteine (Cys) residues, wherein the C-terminal amino acid residue of the N-terminal fragment is cysteine (Cys), wherein the residue immediately preceding the C-terminal Cys residue of the N-terminal fragment is a non-threonine substitution of threonine, wherein the two cysteine residues are separated by four, five or six amino acids and wherein the two cysteine residues can form a disulfide bond;
Y1 is selected from the group consisting of Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn (SEQ ID NO:59) and Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp (SEQ ID NO:60); and
Z1 is selected from the group consisting of Thr-Gly-Ser-Gly-Thr-Pro-NH2 (SEQ ID NO:62), Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2 (SEQ ID NO:63) and Val-Gly-Ser-Lys-Ala-Phe-NH2 (SEQ ID NO:46).

### Claim 2 (depends on 1)

The antagonist of claim 1 wherein X1 comprises NH2-Ala-Cys-X1-X2-X3-X4-Cys (SEQ ID NO: 64), X1 is Asp, Asn, Val or Arg, X2 is Thr, Leu or Phe, X3 is Ala, Gly or Ser and X4 is Ala, Leu, Ile or Val.

### Claim 3 (depends on 2)

The antagonist of claim 2, wherein X1 selected from the group consisting of NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys- (SEQ ID NO: 17), NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-(SEQ ID NO: 18), NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys- (SEQ ID NO: 19), NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys- (SEQ ID NO: 20), NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys- (SEQ ID NO: 21), NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys- (SEQ ID NO: 22), NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-(SEQ ID NO: 23), NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys- (SEQ ID NO: 24), NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys- (SEQ ID NO: 25), NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys- (SEQ ID NO: 26), NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys- (SEQ ID NO: 27), NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-(SEQ ID NO: 28), NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys- (SEQ ID NO: 29), NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys- (SEQ ID NO: 30), NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys- (SEQ ID NO: 31), NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys- (SEQ ID NO: 32), and NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys- (SEQ ID NO: 33).

### Claim 4 (depends on 3)

An antagonist of claim 3 wherein Y1 is Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn (SEQ ID NO: 59).

### Claim 5 (depends on 4)

An antagonist of claim 4 wherein Z1 is Thr-Gly-Ser-Gly-Thr-Pro-NH2 (SEQ ID NO: 62).

### Claim 6 (depends on 3)

An antagonist of claim 3 wherein Y1 is Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp (SEQ ID NO: 60).

### Claim 7 (depends on 6)

An antagonist of claim 6 wherein Z1 is Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2 (SEQ ID NO: 63).

### Claim 8 (depends on 4, 5, 6, 7)

An antagonist of any of claims 4-7, wherein X1 is selected from the group consisting of Ala-Cys-Asp-Thr-Ala-Ala-Cys (SEQ ID NO: 17), Ala-Cys-Val-Leu-Gly-Ala-Cys (SEQ ID NO:21) and Ala-Cys-Asn-Leu-Ser-Ala-Cys (SEQ ID NO:24).

### Claim 9 (depends on 3)

An antagonist of claim 3 selected from the group consisting of Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (SEQ ID NO: 13), Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2 (SEQ ID NO: 14) and Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2 (SEQ ID NO: 15).

### Claim 10 (depends on 1, 9)

A method of treating a condition associated with aberrant levels of CGRP comprising the administration of a calcitonin gene-related peptide antagonist of any one of claim 1 or 9, to an individual, the method comprising administering to the individual an effective amount of the calcitonin gene-related peptide antagonist.

### Claim 11 (depends on 10)

The method of claim 10, wherein the condition is migraine.

### Claim 12 (depends on 1, 9)

A method of treating a headache in an individual, the method comprising administering to the individual an effective amount of a calcitonin gene-related peptide antagonist of any of claim 1 or 9.

### Claim 13 (depends on 12)

The method of claim 12, wherein the headache is migraine.