LLP2A-bisphosphonate conjugates for osteoporosis treatment

Patent metadata

Field	Value
Publication number	US-9561256-B2
Application number	US-201514806398-A
Country	US
Kind code	B2
Filing date	Jul 22, 2015
Priority date	Sep 2, 2010
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

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 α 4 β 1 integrin on mesenchymal stem cells and for the surface of bone.

First claim

What is claimed is:

1. A method of treating a bone disease or bone injury in a subject wherein the bone disease excludes bone cancer, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the formula:

and a pharmaceutically acceptable excipient; 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 method of claim 1 , wherein R 1 is methyl and R 3 is H.

3. The method 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.

4. The method 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).

5. The method 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.

6. The method of claim 1 , wherein the compound has the formula:

7. The method of claim 1 , wherein the method comprises treating a bone injury.

8. The method of claim 7 , wherein the bone injury is a bone fracture.

9. The method of claim 8 , wherein the bone fracture is an osteoporotic fracture.

10. The method of claim 8 , wherein the bone fracture is a stress fracture.

11. The method of claim 1 , wherein the pharmaceutical composition is administered systemically.

12. The method of claim 1 , wherein the pharmaceutical composition is administered locally.

13. The method of claim 7 , wherein the pharmaceutical composition is administered locally at the site of the bone injury.

14. The method of claim 1 , further comprising administering mesenchymal stem cells to the subject.

Assignees

• Univ California

Inventors

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

Classifications

• A61K47/548

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

• 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

• A61K47/64

  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