Regulators of the hedgehog pathway, compositions and uses related thereto

• US 7,476,661 B2
• Filed: 01/23/2006
• Issued: 01/13/2009
• Est. Priority Date: 10/13/1999
• Status: Expired due to Term

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Nikolai Taipale, Anssi Jussi, Chen, James K., Beachy, Philip A.
• Primary Examiner(s): Lewis; Patrick T.
• Application Number:
  US11/338,503
• Publication Number:
  US 20060128639A1
• Time in Patent Office: 1,086 Days
• Field of Search: None
• US Class Current: 514/81
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• 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 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 27/12 : for cataracts
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07J 69/00 : Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom

Abstract

The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

Claims

1. A method for regulating differentiation or proliferation of a cell, comprising administering to a patient a compound represented in the general formulas (I), or (V), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

2. The method of claim 1, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

31. The method of any one of claims 1, 3, 11, 13, 21, or 23, wherein the substituted alkyl that substitutes the tertiary amine is an extraannular substituent.

32. The method of claim 31, wherein the extraannular substituent is hydrophobic.

33. The method of claim 32, wherein the hydrophobic extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, and urea.

34. The method of claim 31, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

35. The method of claim 34, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

36. The method of claim 31, wherein the extraannular substituent incorporates an alkyl substituted with aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, or sulfonamide.

37. The method of claim 36, wherein the extraannular substituent incorporates an alkyl substituted with acylamino.

3. A method for regulating differentiation or proliferation of a cell, comprising administering to a patient a compound represented in the general formulas (II), or unsaturated forms thereof and/or seco-, nor- or home-derivatives thereof:

4. The method of claim 3, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

5. A method for regulating differentiation or proliferation of a cell, comprising administering to a patient a compound represented in the general formulas (III), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

6. The method of claim 5, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

7. A method for regulating differentiation or proliferation of a cell, comprising administering to a patient a compound represented in the general formulas (IV), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

8. The method of claim 7, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

9. A method for regulating differentiation or proliferation of a cell, comprising administering to a patient a compound represented in the general formulas (V), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

10. The method of claim 9, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈.

11. A method for controlling the growth or development of pancreatic tissue, comprising contacting the tissue with a compound represented in the general formulas (I), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

12. The method of claim 11, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

13. A method for controlling the growth or development of pancreatic tissue, comprising contacting the tissue with a compound represented in the general formulas (II), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

14. The method of claim 13, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

15. A method for controlling the growth or development of pancreatic tissue, comprising contacting the tissue with a compound represented in the general formulas (III), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

16. The method of claim 15, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

38. The method of any one of claims 5, 7, 9, 15, 17, 19, 25, 27, or 29, wherein the at least one occurrence of R₉ attached to N that is a substituted alkyl is an extraannular substituent.

39. The method of claim 38, wherein the extraannular substituent is hydrophobic.

40. The method of claim 39, wherein the hydrophobic extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, and urea.

41. The method of claim 38, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

42. The method of claim 41, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

43. The method of claim 38, wherein the extraannular substituent incorporates an alkyl substituted with aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, or sulfonamide.

44. The method of claim 43, wherein the extraannular substituent incorporates an alkyl substituted with acylamino.

17. A method for controlling the growth or development of pancreatic tissue, comprising contacting the tissue with a compound represented in the general formulas (IV), or unsaturated forms thereof and/or seco-. nor- or homo-derivatives thereof:

18. The method of claim 17, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

19. A method for controlling the growth or development of pancreatic tissue, comprising contacting the tissue with a compound represented in the general formulas (V), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

20. The method of claim 19, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈.

21. A method for treating a hyperproliferative disorder, comprising administering to a patient a compound represented in the general formulas (I), or (V), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

22. The method of claim 21, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

23. A method for treating a hyperproliferative disorder, comprising administering to a patient a compound represented in the general formulas (II), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

24. The method of claim 23, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

25. A method for treating a hyperproliferative disorder, comprising administering to a patient a compound represented in the general formulas (III), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

26. The method of claim 25, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

27. A method for treating a hyperproliferative disorder, comprising administering to a patient a compound represented in the general formulas (IV), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

28. The method of claim 27, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₅, for each occurrence, is absent, or represents —

OH, ═

O, or alkyl.

29. A method for treating a hyperproliferative disorder, comprising administering to a patient a compound represented in the general formulas (V), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:

30. The method of claim 29, wherein:

R₂ represents ═

O, sugar, carbamate, ester, carbonate, or alkoxy;

R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₄, for each occurrence, is absent, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈.