Inhibitors of proteasomal activity for stimulating hair growth

• US 20050025734A1
• Filed: 07/19/2004
• Published: 02/03/2005
• Est. Priority Date: 07/10/1998
• Status: Active Grant

• Current Assignee: Osteoscreen IP, LLC
• Original Assignee: Osteoscreen IP, LLC
• Inventors: Garrett, I. Ross, Gutierrez, Gloria, Rossini, Jorge Gianny
• Granted Patent: US 7,175,994 B2
• Time in Patent Office: Days
• US Class Current: 424/70.140
• 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 the proteasome or the production of proteasomal proteins promote hair growth by stimulating 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 treat a mammalian subject for a condition benefited by stimulating hair growth which method comprises administering to said mammalian subject in need of such treatment an effective amount of a pharmaceutical composition comprising

a) a compound that inhibits proteasomal activity or that inhibits the production of proteasome proteins;

and

b) a suitable excipient.

2. The method of claim 1, wherein the pharmaceutical composition further comprises an agent promoting skin tissue growth or infiltration.

3. The method of claim 2, wherein the agent is selected from the group consisting of an epidermal growth factor, a fibroblast growth factor, a platelet-derived growth factor, a transforming growth factor, a parathyroid hormone, a leukemia inhibitory factor, and an insulin-like growth factor.

4. The method of claim 1, wherein the subject is a human.

5. The method of claim 1, wherein the condition to be treated is selected from the group consisting of male pattern baldness, alopecia caused by chemotherapy, hair thinning due to aging, and genetic disorders.

6. The method of claim 1, wherein the subject is a non-human mammal.

7. The method of claim 6, wherein said hair growth provides additional protection from cold temperatures.

8. The method of claim 1, wherein the hair growth is due to thickened hair sheath diameter, increased hair diameter, differentiation of quiescent hair follicles into more mature forms, increased rate of growth in hair length and/or thickness, or the appearance of proliferation of new hair follicles.

9. The method of claim 1, wherein the benefit is primarily cosmetic.

10. The method of claim 1, wherein the pharmaceutical composition is administered topically.

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

12. The method of claim 11, wherein the pharmaceutical composition is administered is administered using a transdermal patch.

13. The method of claim 10 or 11, wherein the pharmaceutical composition is administered in a lotion, a gel, or an ointment.

14. The method of claim 10 or 11, wherein the pharmaceutical composition is administered in a liposome.

15. The method of claim 11 or 12, wherein the pharmaceutical composition further comprises a polyglycol.

16. The method of claim 15, wherein the polyglycol is propylene glycol.

17. The method of claim 1, wherein the pharmaceutical composition is administered in an aerosol.

18. The method of claim 1, wherein the pharmaceutical composition is administered parenterally.

19. The method of claim 1, wherein the pharmaceutical composition is administered subcutaneously.

20. The method of claim 1, wherein the compound inhibits the trypsin-like or peptidyl-glutamyl peptide hydrolytic (PGPH) activity of the proteasome.

21. The method of claim 1, wherein the compound is lactacystin, a peptidyl aldehyde, or a peptidyl epoxy ketone.

22. The method of claim 1, wherein said compound is MG-132, MG-115, or MG-101 (calpain inhibitor 1).

23. The method of claim 1, wherein the compound inhibits the chymotrypsin-like activity of the proteasome.

24. The method of claim 1, wherein the compound is a peptide having at least two amino acids.

25. The method of claim 23, wherein the compound is a peptide having at least three amino acids and a C-terminal functional group that reacts with the threonine residue of the chymotrypsin-like catalytic site of the proteasome.

26. The method of claim 25, 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).

27. The method of claim 26, 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.

28. The method of claim 23, wherein the peptide is a peptide α

′

,β

′

-epoxyketone.

29. The method of claim 28, wherein the peptide α

′

,β

′

-epoxyketone has at least four amino acids.

30. The method of claim 28, wherein the c-terminus amino acid of the peptide α

′

,β

′

-epoxyketone is a hydrophobic amino acid.

31. The method of claim 30, wherein the hydrophobic amino acid is leucine or phenylalanine.

32. The method of claim 23, wherein the peptide α

′

,β

′

-epoxyketone has the following formula;

33. The method of claim 32 wherein each of R, R¹, R² and R³ is independently selected from the group consisting of

34. The method of claim 32, wherein R² and R³ are

35. The method of claim 32, wherein the peptide α

′

,β

′

-epoxyketone has the following stereo-configuration;

36. The method of claim 28, wherein the peptide α

′

,β

′

-epoxyketone has the following formula;

37. The method of claim 36, wherein the peptide α

′

,β

′

-epoxyketone has the following stereo-configuration;

38. The method of claim 37, wherein the peptide α

′

,β

′

-epoxyketone is

39. The method of claim 24, wherein the compound is selected from the group consisting of

40. The method of claim 39, wherein the compound is pyrazylcarbonyl-Phe-Leu-Boronate (PS-341).

41. The method of claim 23, wherein the compound has the following formula:

42. The method of claim 41, 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.

43. The method of claim 41, wherein X is protected.