Inhibitors of proteasomal activity for stimulating hair growth

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;

b) a suitable excipient; and

c) an agent promoting skin tissue growth or infiltration.

2. The method of claim 1 , 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.

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

4. 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.

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

6. The method of claim 5 , wherein said hair growth provides additional protection from cold temperatures.

7. 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.

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

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

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

11. The method of claim 10 , wherein the pharmaceutical composition is administered is administered using a transdermal patch.

12. The method of claim 9 or 10 , wherein the pharmaceutical composition is administered in a lotion, a gel, or an ointment.

13. The method of claim 9 or 10 , wherein the pharmaceutical composition is administered in a liposome.

14. The method of claim 10 or 11 , wherein the pharmaceutical composition further comprises a polyglycol.

15. The method of claim 14 , wherein the polyglycol is propylene glycol.

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

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

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

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

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

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

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

23. The method of claim 22 , 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.

24. The method of claim 23 , 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 ).

25. The method of claim 24 , 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.

26. The method of claim 23 , wherein the peptide is a peptide α′,β′-epoxyketone.

27. The method of claim 26 , wherein the peptide α′,β′-epoxyketone has at least four amino acids.

28. The method of claim 26 , wherein the c-terminus amino acid of the peptide α′,β′-epoxyketone is a hydrophobic amino acid.

29. The method of claim 28 , wherein the hydrophobic amino acid is leucine or phenylalanine.

30. The method of claim 26 , wherein the peptide α′,β′-epoxyketone has the following formula:

wherein R is selected from the group consisting of

31. The method of claim 30 , wherein the peptide α′,β′-epoxyketone has the following stereo-configuration:

32. The method of claim 31 , wherein the peptide α′,β′-epoxyketone is

33. The method of claim 22 , wherein the peptide α′,β′-epoxyketone has the following formula:

wherein each of R, R 1 , R 2 and R 3 is a hydrophobic substituent.

34. The method of claim 33 wherein each of R, R 1 , R 2 and R 3 is independently selected from the group consisting of

35. The method of claim 33 , wherein R 2 and R 3 are

and the compound is selected from the group consisting of

36. The method of claim 33 , wherein the peptide α′,β′-epoxyketone has the following stereo-configuration:

37. The method of claim 22 , 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.

38. The method of claim 37 , wherein R contains a substituted group selected from the group consisting of a halo group, —OR, —SR, —NR 2 , ═O, —COR, —OCOR, —NHCOR, —NO 2 , —CN, and —CF 3 .

39. The method of claim 37 , wherein X is protected.

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

41. The method of claim 40 , wherein the compound is selected from the group consisting of

epoxomicin, pyrazylcarbonyl-Phe-Leu-Boronate (PS-341), tri-leucine vinyl sulfone (NLVS), N-carbobenzoyl-Ile-Glu-(OtBu)-Ala-Leu-CHO (PSI), and PSI epoxide, lactacystin, and a peptidyl aldehyde.

42. The method of claim 41 , wherein the compound is pyrazylcarbonyl-Phe-Leu-Boronate (PS-341).