Methods for treating conditions modulated by lactosylceramide

• US 6,511,979 B1
• Filed: 07/22/1999
• Issued: 01/28/2003
• Est. Priority Date: 07/27/1998
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chatterjee, Subroto
• Primary Examiner(s): COOK, REBECCA
• Application Number:
  US09/359,023
• Time in Patent Office: 1,286 Days
• Field of Search: 514/237.8, 514/315, 514/428
• US Class Current: 514/237.8
• 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 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention includes methods for treatment and prophylaxis of conditions associated with lactosylceramide. The methods generally provide for administration to a mammal, particularly a human, of a therapeutically effective amount of a compound that increases enzymatic activity of UDPGal:GlcCerβ1→4 galactosylceramide (GalT-2). In vitro and in vivo assays for detecting compounds with therapeutic capacity to modulate GalT-2 are also provided.

Claims

1. A method for treating a condition modulated by lactosylceramide in a mammal suffering from or susceptible to the condition, the method comprising administering to the mammal a therapeutically effective amount of a levorotatory GalT-2 enhancing compound.

2.The method of claim 1 wherein the insufficient cell proliferation is diagnostic of the condition.

2. The method of claim 1 or 2 wherein the condition is any one of nervous system degeneration, a wound, or an ulcer.

19. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the GalT-2 enhancing compound is co-administered with at least one platelet derived growth factor (PDGF), oxidized low density lipoprotein (ox-LDL), transforming growth factor alpha (TNF-α

2) or another GalT-2 enhancing compound.

20. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound enhances cell proliferation by at least 25% in a standard in vitro cell proliferation assay.

21. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound enhances cell adhesion by at least 25% in a standard in vitro cell adhesion assay.

22. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound exhibits an EC₅₀ of about 1 μ

m or less in a standard in vitro GalT-2 enzyme assay.

23. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound exhibits an IC₅₀ of about 0.001 μ

m or less in a standard in vitro GbOse₄ Cer assay.

24. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound is levorotatory and is represented by the following Formula I:

wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁-C₆ alkyl with or without a substituent, and further wherein R and R¹ may be joined to form a 5, 6 or 7-membered ring;

R² is selected from the group consisting of branched or straight-chained C₆-C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆-C₂₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁-C₄ alkoxy, methylenedioxy, C₁-C₄ mercapto, amino or substituted amino in which the amino substituent may be C₁-C₄ alkyl.

27. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound is levorotatory and is selected from the group consisting of:

1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-piperdino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol;

1-morpholino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene; and

1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.

28. The method of any one of claims 1, 2, 14, 15, 16, or 17, wherein the compound is L-PDMP.

3. The method of claim 3, wherein the GalT-2 enhancing compound is co-administered with at least one platelet derived growth factor (PDGF), oxidized low density lipoprotein (ox-LDL), transforming growth factor alpha (TNF-α

2) or another GalT-2 enhancing compound .

4. The method of claim 3, wherein the compound enhances cell proliferation by at least 25% in a standard in vitro cell proliferation assay.

5. The method of claim 3, wherein the compound enhances cell adhesion by at least 25% in a standard in vitro cell adhesion assay.

6. The method of claim 3, wherein the compound exhibits an EC₅₀ of about 1 μ

m or less in a standard in vitro GalT-2 enzyme assay.

7. The method of claim 3, wherein the compound exhibits an IC₅₀of about 0.001 μ

m or less in a standard in vitro GbOse₄ Cer assay.

8. The method of claim 3, wherein the compound is levorotatory and is represented by the following Formula I:

wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁-C₆ alkyl with or without a substituent, and further wherein R and R¹ are optionally joined to form a 5, 6 or 7-membered ring;

R² is selected from the group consisting of branched or straight-chained C₆-C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆-C₂₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁-C₄ alkoxy, methylenedioxy, C₁-C₄ mercapto, amino or substituted amino in which the amino substituent is C₁-C₄ alkyl.

11. The method of claim 3, wherein the compound is levrorotatory and is selected from the group consisting of:

1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-piperdino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol;

1-morpholino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene; and

1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.

12. The method of claim 3, wherein the compound is L-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP).

9. The method of claim 9 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

10. The method of claim 9 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

13. A method for increasing angiogenesis in a mammal comprising administering to the mammal one or more levorotatory GalT-2 enhancing compounds in an amount sufficient to increase angiogenesis in the mammal.

14. The method of claim 14, wherein the increased cell proliferation is in any one of brain, eye, heart, kidney or vasculature.

15. The method of claim 14, wherein the GalT-2 enhancing compound is administered to the mammal by a stent.

16. The method of claim 14, wherein the GalT-2 enhancing compound is administered to the mammal orally, intramuscularly, topically, intraoculary or intraperitoneally.

17. The method of claim 14, wherein said levorotary GalT-2 enhancing compound is L-phenyl-2-decanolyamino-3-morpholino-1-proponal.

18. The method of claim 14 or 18, wherein said method is used to treat ischemia.

25. The method of claim 25 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

26. The method of claim 25 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

29. A method for treating a mammal suffering from or susceptible to insufficient cell proliferation or cell adhesion, comprising administering to the mammal a therapeutically effective amount of a levrorotatory compound of the following Formula I:

wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁-C₆ alkyl with or without a substituent, and further wherein R and R¹ are optionally joined to form a 5, 6 or 7-membered ring;

R² is selected from the group consisting of branched or straight-chained C₆-C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆-C₂₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁-C₄ alkoxy, methylenedioxy, C₁-C₄ mercapto, amino or substituted amino in which the amino substituent may be C₁-C₄ alky.

30. The method of claim 30 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

31. The method of claim 30 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

32. The method of claim 30 wherein the levrorotatory compound is selected from the group consisting of L-enantiomers of:

1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-piperidino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol;

1-morpholino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene;

1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene; and

trans-1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.

33. A method for treating a condition modulated by lactosylceramide in a mammal suffering from or susceptible to the condition, the method comprising administering to the mammal a therapeutically effective amount of a levorotatory GalT-2 enhancing compound, wherein the condition is a bacterial infection or atherosclerosis.

34. A method for increasing MAP Kinase activity in a mammal comprising administering to the mammal a therapeutically effective amount of a levorotary GalT-2 enhancing compound.

35. The method according to claim 35, wherein said levorotary GalT-2 enhancing compound comprises L-phenyl-2-decanolyamino-3-morpholino-1-proponal.