Inhibitors of proteasomal activity for stimulating hair growth

• US 6,884,769 B1
• Filed: 04/25/2000
• Issued: 04/26/2005
• Est. Priority Date: 07/10/1998
• Status: Expired due to Term

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: OsteoScreen, Inc.
• Inventors: Mundy, Gregory R., Garrett, I. Ross, Rossini, Jorge Gianny
• Primary Examiner(s): GITOMER, RALPH J
• Application Number:
  US09/558,973
• Time in Patent Office: 1,827 Days
• Field of Search: 514/2, 514/18, 548/453, 435/23, 435/69.2
• US Class Current: 514/8.8
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61Q 7/00 Preparations for affecting hair growth

Abstract

Compounds that inhibit the activity of NF-κB or inhibit the activity of the proteasome or both promote bone formation and hair growth and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyrdidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation; they also stimulate the production of hair follicles and are thus useful in stimulating hair growth, including hair density, in subject where this is desirable.

Claims

1. A method to enhance bone formation in a vertebrate animal, which method comprises administering to a vertebrate animal in need of such treatment an effective amount of a compound that inhibits the chymotrypsin-like activity of the proteasome.

2. The method of claim 1, wherein said compound being a peptide having at least 3 amino acids and a c-terminal functional group that reacts with the threonine residue of the chymotrypsin-like catalytic site of the proteasome, or a compound having the following formula:

wherein the warhead reacts irreversibly with the catalytic chymotrypsin site of the proteasome;

A is independently CO—

NH or isostereomer thereof;

R is independently a hydrocarbyl;

X is a polar group; and

n=0-2,

whereby bone formation is enhanced in said vertebrate animal.

3. The method of claim 2, wherein the compound is a peptide having at least 3 amino acids and a c-terminal functional group that reacts with the threonine residue of the chymotrypsin-like catalytic site of the proteasome.

4. The method of claim 3, wherein the c-terminal functional group is selected from the group consisting of an epoxide, a —

B(OR)₂ group, a —

S(OR)₂ group and a —

SOOR group, wherein R is H, an alkyl (C_1-6) or an aryl (C_1-6).

5. The method of claim 4, wherein the functional group is an epoxide that forms a morpholino ring with the threonine residue of the chymotrypsin-like catalytic site of the proteasome.

6. The method of claim 2, wherein the peptide is a peptide α

′

,β

′

-epoxyketone.

7. The method of claim 6, wherein the peptide α

′

,β

′

-epoxyketone has at least 4 amino acids.

8. The method of claim 7, wherein the c-terminus amino acid of the peptide α

′

,β

′

-epoxyketone is a hydrophobic amino acid.

9. The method of claim 8, wherein the hydrophobic amino acid is leucine or phenylalanine.

10. The method of claim 6, wherein the peptide α

′

,β

′

-epoxyketone has the following formula;

wherein R or R^I is selected from the group consisting of

11. The method of claim 10, wherein the compound is selected from the group consisting of

12. The method of claim 10, wherein the peptide α

′

,β

′

-epoxyketone has the following stereo-configuration;

13. The method of claim 6, wherein the peptide α

′

,β

′

-epoxyketone has the following formula;

wherein R is selected from the group consisting of

14. The method of claim 13, wherein the peptide α

′

,β

′

-epoxyketone has the following stereo-configuration;

15. The method of claim 14, wherein the peptide α

′

,β

′

-epoxyketone is

16. The method of claim 2, wherein the compound has the following formula:

wherein the warhead reacts irreversibly with the catalytic chymotrypsin site of the proteasome;

A is independently CO—

NH or isostereomer thereof;

R is independently a hydrocarbyl;

X is a polar group; and

n=0-2.

17. The method of claim 16, wherein R contains a substituted group selected from the group consisting of a halo group, —

OR, —

SR, —

NR₂, ═

O, —

COR, —

OCOR, —

NHCOR, —

NO₂, —

CN, and —

CF₃.

18. The method of claim 16, wherein X is protected.

19. The method of claim 1, wherein the subject is characterized by a condition selected from the group consisting of osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, metastatic bone disease, and osteolytic bone disease.

20. The method of claim 1, which further comprises administering to the subject an agent that promotes bone growth or that inhibits bone resorption.

21. The method of claim 20, wherein the agent is selected from the group consisting of a bone morphogenetic factor, an anti-resorptive agent, an osteogenic factor, a cartilage-derived morphogenetic protein, a growth hormone, an estrogen, a bisphosphonate, a statin and a differentiating factor.

22. The method of claim 1, wherein the vertebrate animal is a human.

23. The method of claim 1, wherein the vertebrate animal is a non-human mammal.