# US 10,501,518 B2 · Alpha-/beta-polypeptide analogs of parathyroid hormone (PTH) and method of using same

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- Number: US 10,501,518 B2
- Document ID: US10501518B2
- Status: Granted
- Kind: B2
- Application number: 14/312,012
- Filed: 2014-06-23
- Published: 2014-12-25
- Granted: 2019-12-10
- Earliest claimed: 2013-06-23
- Assignees: Wisconsin Alumni Research Foundation; The General Hospital Corporation
- Applicants: Wisconsin Alumni Research Foundation; The General Hospital Corporation
- Inventors: Samuel H. Gellman; Ross W. Cheloha; Thomas J. Gardella
- Web page: https://patentgrep.com/patent/US10501518B2

## CPC

- C07K 14/635: Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
- A61P 5/18: of the parathyroid hormones
- 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

Described are polypeptide analogs of parathyroid hormone (PTH) that include at least two non-adjacent β-amino acid residues in place of a naturally occurring α-amino acid residues. Also described are pharmaceutical compositions useful for treating hypoparathyroidism that contain the analogs and methods of using the analogs to treat hypoparathyroidism.

## Claims

### Claim 1

An isolated, unnatural peptide analog comprising:
PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist- or inverse agonist effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 or PTHR-2 agonist-, or inverse agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 or PTHR-2 agonist- or inverse agonist-effective fragment of M-PTH, BA058, or a PTHR-1 or PTHR-2 agonist-, or inverse agonist-effective fragment of BA058, in which at least five non-adjacent α-amino acid residues are replaced with β-amino acid residues; and
salts thereof.

### Claim 2 (depends on 1)

The peptide analog of claim 1, in which the at least five α-amino acid residues are replaced with five β-amino acid residues having the same side-chain as the α-amino acid residues they replace.

### Claim 3 (depends on 1)

The peptide analog of claim 1, in which at least one of the at least five non-adjacent α-amino acid residues is replaced with a cyclically constrained β-amino acid residue.

### Claim 4 (depends on 1)

The peptide analog of claim 1, in which the at least five β-amino acid residues appear in a pattern comprising αβαβαβαβαβ, ααβααβααβααβααβ, αααβαααβαααβαααβαααβ, and ααβαααβααβαααβααβ.

### Claim 5 (depends on 1)

The peptide analog of claim 1, comprising thirty four (34) N-terminal residues of a mammalian parathyroid hormone, PTH(1-34), in which at least five non-adjacent α-amino acid residues are replaced with a β-amino acid residues.

### Claim 6 (depends on 5)

The peptide analog of claim 5, in which the at least five α-amino acid residues are replaced with three β-amino acid residues having the same side-chain as the α-amino acid residues they replace.

### Claim 7 (depends on 5)

The peptide analog of claim 5, in which at least one of the at least five non-adjacent α-amino acid residues is replaced with a cyclically constrained β-amino acid residue.

### Claim 8 (depends on 5)

The peptide analog of claim 5, in which the at least three β-amino acid residues appear in a pattern comprising αβαβαβαβαβ, ααβααβααβααβααβ, αααβαααβαααβαααβαααβ, and ααβαααβααβαααβααβ.

### Claim 9 (depends on 1)

The peptide analog of claim 1, selected from the group consisting of
(SEQ. ID. NO: 5)
A5: SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-NH2,
(SEQ. ID. NO: 6)
B5: SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVQNF-NH2,
(SEQ. ID. NO: 7)
C5: SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-NH2,
(SEQ. ID. NO: 8)
D5: SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-NH2,
(SEQ. ID. NO: 9)
D6: SVSEIQLMHNLGKWLNSMERVEWLRKKLQDVHNF-NH2,
and
(SEQ. ID. NO: 10)
D7: SVSEIQLMHNLGKWLNSMERVEWLRKKLQDVHNF-NH2
wherein bold, underlined residues designate β3 residues having a side chain of the α residue indicated by the letter, and salts thereof.

### Claim 10 (depends on 1)

The peptide analog of claim 1, which is an agonist of parathyroid hormone receptor-1.

### Claim 11

A pharmaceutical composition for treating hypoparathyroidism, the composition comprising a parathyroid hormone receptor agonist-effective amount of PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist-effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 or PTHR-2 agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 or PTHR-2 agonist-effective fragment of M-PTH, BA058, or a PTHR-1 or PTHR-2 agonist-effective fragment of BA058, in which at least five non-adjacent α-amino acid residues are replaced with β-amino acid residues, in combination with a pharmaceutically suitable carrier.

### Claim 12 (depends on 11)

A method of treating hypoparathyroidism in a mammalian subject, including a human subject, the method comprising administering to the subject a parathyroid hormone receptor agonist-effective amount of a pharmaceutical composition as recited in claim 11.