Vitamin D analogs for obesity prevention and treatment

• US 20050119242A1
• Filed: 11/24/2004
• Published: 06/02/2005
• Est. Priority Date: 11/25/2003
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Thomson, Brian, Ahrens, Jamie M., DeLuca, Hector F., Clagett-Dame, Margaret, Ntambi, James M.
• Granted Patent: US 8,188,064 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Methods for treating and preventing obesity, inhibiting adipocyte differentiation, inhibiting increased SCD-1 gene transcription, and/or reducing body fat in a subject include administering at least one analog of 1α,25-dihydroxyvitamin D₃ or 1α,25-dihydroxyvitamin D₂ or a pharmaceutical composition that includes such an analog to a subject in need thereof. The analog may be a 19-nor vitamin D analog such as a compound of formula IA, a compound of formula IB, or a mixture thereof where the variables R¹, R², and R³ have the values described herein.

Claims

1. A method for preventing or treating obesity, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal subject, comprising administering to the animal subject, an effective amount of an analog of 1α

,25-dihydroxyvitamin D₃ or 1α

,25-dihydroxyvitamin D₂ or a pharmaceutical composition comprising the analog, wherein the analog administered to the subject inhibits adipocyte differentiation, inhibits gene transcription, and/or reduces body fat in the animal subject, and further wherein, the analog is a compound other than (20S)-2-methylene-19-nor-1α

,25-dihydroxyvitamin D₃.

2. The method of claim 1, wherein the analog of 1α

,25-dihydroxyvitamin D₃ or 1α

,25-dihydroxyvitamin D₂ is a 19-nor vitamin D analog.

3. The method of claim 2, wherein the 19-nor vitamin D analog is a 2-alkylidene 19-nor vitamin D analog.

4. The method of claim 3, wherein the 2-alkylidene 19-nor vitamin D analog is a 2-methylene 19-nor vitamin D analog.

5. The method of claim 4, wherein the 2-methylene 19-nor vitamin D analog is selected from (20S) 2-methylene 19-nor vitamin D analogs, (20R) 2-methylene 19-nor vitamin D analog, or combinations thereof.

6. The method of claim 1, wherein the analog is selected from a compound of formula IA, a compound of formula IB, or is a combination thereof

7. The method of claim 6, wherein R³ is H.

8. The method of claim 6, wherein R² is a straight chain alkyl group.

9. The method of claim 6, wherein R² and R³ join together to form a group of formula IC.

10. The method of claim 1, wherein the analog is selected from a compound of formula IIA, a compound of formula IIB, or is a combination thereof

11. The method of claim 10, wherein R¹ is selected from straight or branched chain alkyl groups having from 2 to 7 carbon atoms, straight or branched chain alkenyl groups having from 2 to 7 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 2 to 6 carbon atoms, or straight or branched chain hydroxy-substituted alkenyl groups having from 2 to 6 carbon atoms.

12. The method of claim 10, wherein R¹ is selected from straight or branched chain alkyl groups having from 2 to 7 carbon atoms, straight or branched chain alkenyl groups having from 2 to 7 carbon atoms, or straight or branched chain hydroxy-substituted alkenyl groups having from 2 to 6 carbon atoms.

13. The method of claim 10, wherein R¹ is selected from one of the following groups

14. The method of claim 1, wherein the analog has the formula IID

15. The method of claim 1, wherein the analog has the formula IIE

16. The method of claim 1, wherein the analog has the formula IIF

17. The method of claim 1, wherein the analog has the formula IIG

18. The method of claim 1, wherein the analog has the formula IIH

19. The method of claim 1, wherein the analog has the formula IIJ

20. The method of claim 1, wherein the analog has the formula IIK

21. The method of claim 1, wherein the analog has the formula IIL

22. The method of claim 1, wherein the analog has the formula IIM

23. The method of claim 1, wherein the analog has the formula IIN

24. The method of claim 1, wherein the analog has the formula IIO

25. The method of claim 1, wherein the analog has the formula IIP

26. The method of claim 1, wherein the analog has the formula IIQ

27. The method of claim 1, wherein the analog has the formula IIR

28. The method of claim 1, wherein the analog has the formula IIS

29. The method of claim 1, wherein the analog has the formula IIT

30. The method of claim 1, wherein the analog has the formula IIU

31. The method of claim 1, wherein the analog has the formula IIV

32. The method of claim 1, wherein the analog has the formula IIW

33. The method of claim 1, wherein the animal is selected from a rodent, a primate, a bovine, an equine, a canine, a feline, an ursine, a porcine, a rabbit, or a guinea pig.

34. The method of claim 33, wherein the animal is a mouse or is a rat.

35. The method of claim 33, wherein the animal is a human.

36. The method of claim 33, wherein the animal is a post menopausal human female.

37. The method of claim 1, wherein the analog is administered orally, parenterally, transdermally, topically, intranasally, rectally, or intravaginally.

38. The method of claim 37, wherein the analog is administered orally to the animal subject.

39. The method of claim 1, wherein the amount of the analog administered to the animal subject ranges from 0.001 μ

g per day to 100 mg per day.

40. The method of claim 39, wherein the amount of the analog administered to the animal subject ranges from 0.10 μ

g to 1,000 μ

g per day.

41. A method for inhibiting PPARγ

or C/EBPα

gene transcription in an animal subject comprising administering to the animal subject, an effective amount of an analog of 1α

,25-dihydroxyvitamin D₃ or 1α

,25-dihydroxyvitamin D₂ or a pharmaceutical composition comprising the analog, wherein the analog administered to the subject inhibits PPARγ

or C/EBPα

gene transcription gene in the animal subject, and further wherein, the analog is a compound other than (20S)-2-methylene-19-nor-1α

,25-dihydroxyvitamin D₃.

42. The method of claim 41, wherein the analog of 1α

,25-dihydroxyvitamin D₃ or 1α

,25-dihydroxyvitamin D₂ is a 19-nor vitamin D analog.

43. The method of claim 42, wherein the 19-nor vitamin D analog is a 2-alkylidene 19-nor vitamin D analog.

44. The method of claim 43, wherein the 2-alkylidene 19-nor vitamin D analog is a 2-methylene 19-nor vitamin D analog.

45. The method of claim 44, wherein the 2-methylene 19-nor vitamin D analog is selected from (20S) 2-methylene 19-nor vitamin D analogs, (20R) 2-methylene 19-nor vitamin D analog, or combinations thereof.

46. The method of claim 41, wherein the analog is selected from a compound of formula IA, a compound of formula IB, or is a combination thereof

47. The method of claim 46, wherein R³ is H.

48. The method of claim 46, wherein R² is a straight chain alkyl group.

49. The method of claim 46, wherein R² and R³ join together to form a group of formula IC.

50. The method of claim 41, wherein the analog is selected from a compound of formula IIA, a compound of formula IIB, or is a combination thereof

51. The method of claim 50, wherein R¹ is selected from straight or branched chain alkyl groups having from 2 to 7 carbon atoms, straight or branched chain alkenyl groups having from 2 to 7 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 2 to 6 carbon atoms, or straight or branched chain hydroxy-substituted alkenyl groups having from 2 to 6 carbon atoms.

52. The method of claim 50, wherein R¹ is selected from straight or branched chain alkyl groups having from 2 to 7 carbon atoms, straight or branched chain alkenyl groups having from 2 to 7 carbon atoms, or straight or branched chain hydroxy-substituted alkenyl groups having from 2 to 6 carbon atoms.

53. The method of claim 46, wherein R¹ is selected from one of the following groups

54. The method of claim 41, wherein the animal is selected from a rodent, a primate, a bovine, an equine, a canine, a feline, an ursine, a porcine, a rabbit, or a guinea pig.

55. The method of claim 54, wherein the animal is a human.

56. The method of claim 41, wherein the analog is administered orally, parenterally, transdermally, topically, intranasally, rectally, or intravaginally.

57. The method of claim 41, wherein the amount of the analog administered to the animal subject ranges from 0.001 μ

g per day to 100 mg per day.

58. The method of claim 41, wherein the amount of the analog administered to the animal subject ranges from 0.10 μ

g to 1,000 μ

g per day.