LLP2A-bisphosphonate conjugates for osteoporosis treatment

Patent metadata

Field	Value
Publication number	US-10494401-B2
Application number	US-201615387380-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Sep 2, 2010
Publication date	Dec 3, 2019
Grant date	Dec 3, 2019

Abstract

The present invention provides compounds and pharmaceutical compositions of a peptidomimetic ligand, e.g. LLP2A, conjugated with a bisphosphonate drug, e.g. Alendronate. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of osteoporosis and for the promotion of bone growth due to their specificity for the α4β1 integrin on mesenchymal stem cells and for the surface of bone.

First claim

What is claimed is:

1. A compound having the formula:

wherein
R 1 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;
R 3 is selected from the group consisting of H, C 1-6 alkyl and C 3-8 cycloalkyl;
Z is a peptide having 3-20 independently selected amino acids, wherein at least one amino acid is selected from the group consisting of an unnatural amino acid and a D-amino acid;
L is a linker; and
D is a bisphosphonate drug.

2. The compound of claim 1 , wherein R 1 is methyl and R 3 is H.

3. The compound of claim 1 , wherein peptide Z has the formula:
-X AA1 -X AA2 -X AA3 -(X AA4 ) p -
wherein
X AA1 is selected from the group consisting of a hydrophobic amino acid and derivatives of lysine, homolysine (Hly), ornithine (Orn) and α,γ-diaminobutyric acid (Dbu);
X AA2 is a negatively charged amino acid;
X AA3 is a hydrophobic amino acid;
X AA4 is selected from the group consisting of a naturally-occurring amino acid, an unnatural amino acid, and a D-amino acid; and
subscript p is 0 or 1.

4. The compound of claim 3 , wherein
X AA1 is lysine-A38 (Lys38);
X AA2 is α-aminohexanedioic acid (Aad);
X AA3 is a hydrophobic amino acid; and
subscript p is 0.

5. The compound of claim 1 , wherein peptide Z is selected from the group consisting of Lys38-Aad-D-Phe, -Lys38-Aad-Ach, -Lys38-Aad-D-Nal-2, -Lys38-Aad-Ile, -Lys38-Aad-Val, and Lys38-Aad-Leu.

6. The compound of claim 1 , wherein peptide Z is -Lys38-Aad-Ach.

7. The compound of claim 1 , wherein linker L comprises at least one of N-(8-amino-3,6-dioxa-octyl)succinamic acid (EBES) and polyethylene glycol (PEG).

8. The compound of claim 1 , wherein linker L is selected from the group consisting of:

wherein k is from 0 to 6.

9. The compound of claim 1 , wherein D has the formula:

wherein
R 4 is selected from the group consisting of H, OH and halogen;
R 5 is selected from the group consisting of H and C 1-6 alkyl; and
subscript t is from 1 to 6.

10. The compound of claim 1 , wherein D has the formula selected from the group consisting of:

11. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

12. A compound having the formula:

13. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable excipient.

14. A method of treating osteoporosis, comprising administering the compound of claim 1 to a subject having osteoporosis.

15. A method of promoting bone growth in a subject, comprising administering to the subject the compound of claim 1 .

16. A method of treating low bone mass in a subject, comprising administering to the subject the compound of claim 1 .

17. A method of treating osteoporosis, comprising administering the compound of claim 12 to a subject having osteoporosis.

18. A method of treating a bone injury in a subject, comprising administering to the subject the compound of claim 12 .

19. The method of claim 18 , wherein the bone injury is a bone fracture.

Assignees

• Univ California

Inventors

• Lam Kit S
• Liu Ruiwu
• Yao Wei
• Lane Nancy

Classifications

• A61P19/10

  for osteoporosis · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K47/548

  Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544) · CPC title

• A61K47/64

  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 title