Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 20050085519A1
• Filed: 07/29/2002
• Published: 04/21/2005
• Est. Priority Date: 07/27/2001
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Price, Stephen, Boyd, Edward Andrew, Rubin, Lee L., Guicherit, Oivin
• Granted Patent: US 8,354,397 B2
• Time in Patent Office: Days
• US Class Current: 514/367
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 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 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 263/57 Aryl or substituted aryl radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Claims

1. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule represented in the general formula (I):

2. The method of claim 1, wherein at least one of Z and X is not a direct bond.

3. The method of claim 1, wherein X-Y-Z includes an amide, urea, or sulfonamide.

4. The method of claim 1, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and preferably represents NH.

5. The method of claim 1, wherein R₁ includes an aryl or heteroaryl ring, optionally substituted with from 1-5 substituents.

6. The method of claim 5, wherein the substituents on R₁ are selected from nitro, halogen, cyano, lower alkyl, acylamino (e.g., R₈—

C(═

O)NH—

), alkoxy, alkylamino, a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, and heteroaryl fused to the aryl or heteroaryl ring.

7. The method of claim 1, wherein X and the ring comprising A are disposed on Ar in a meta relationship.

8. The method of claim 1, wherein R₂ represents from 1-4 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl group, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, J-R₈, J-OH, J-lower alkyl, J-lower alkenyl, J-R₈, J-SH, J-NH₂, protected forms of the above, or any two R₂, when occurring more than once in a cyclic or polycyclic structure, can be taken together form a 4- to 8-membered cycloalkyl, aryl, or heteroaryl.

9. The method of claim 8, wherein R₂ represents from 1-4 substituents selected from halogen, cyano, nitro, alkoxy, amino, acylamino (e.g., R₈—

C(═

O)NH—

), a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl fused to G, and substituted or unsubstituted lower alkyl.

10. The method of claim 1, wherein the cell has a phenotype of ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function.

11. The method of claim 1, wherein the hedgehog antagonist inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

12. The method of claim 1, wherein the hedgehog antagonist inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

13. The method of claim 1, wherein the cell is contacted with the hedgehog antagonist in vitro.

14. The method of claim 1, wherein the cell is contacted with the hedgehog antagonist in vivo.

15. The method of claim 1, wherein the hedgehog antagonist is administered as part of a therapeutic or cosmetic application.

16. The method of claim 15, wherein the therapeutic or cosmetic application is selected from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primative gut, regulation of hematopoietic function, and regulation of skin and hair growth.

36. The method of claim 1 or 17, wherein the cell has aptc loss-of-function phenotype, hedgehog gain-of-function phenotype, or a smoothened gain-of-function phenotype.

17. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule represented in the general formula (II):

18. The method of claim 17, wherein at least one of Z and X is not a direct bond.

19. The method of claim 17, wherein X-Y-Z includes an amide, urea, or sulfonamide.

20. The method of claim 17, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and preferably represents NH.

21. The method of claim 17, wherein R₁ includes an aryl or heteroaryl ring, optionally substituted with from. 1-5 substituents.

22. The method of claim 21, wherein the substituents on R₁ are selected from nitro, halogen, cyano, lower alkyl, acylamino (e.g., R₈-C(═

O)NH—

), alkoxy, alkylamino, a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, and heteroaryl fused to the aryl or heteroaryl ring.

23. The method of claim 17, wherein R₂ represents from 1-4 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl group, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, J-R₈, J-OH, J-lower alkyl, J-lower alkenyl, J-R₈, J-SH, J-NH₂, protected forms of the above, or any two R₂, when occurring more than once in a cyclic or polycyclic structure, can be taken together form a 4- to 8-membered cycloalkyl, aryl, or heteroaryl.

24. The method of claim 23, wherein R₂ represents from 1-4 substituents selected from halogen, cyano, nitro, alkoxy, amino, acylamino, a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl fused to G, and substituted or unsubstituted lower alkyl.

25. The method of claim 17, wherein the cell has a phenotype of ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function.

26. The method of claim 17, wherein the hedgehog antagonist inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

27. The method of claim 17, wherein the hedgehog antagonist inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

28. The method of claim 17, wherein the cell is contacted with the hedgehog antagonist in vitro.

29. The method of claim 17, wherein the cell is contacted with the hedgehog antagonist in vivo.

30. The method of claim 17, wherein the hedgehog antagonist is administered as part of a therapeutic or cosmetic application.

31. The method of claim 30, wherein the therapeutic or cosmetic application is selected from the group consisting of regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primative gut, regulation of hematopoietic function, and regulation of skin and hair growth.

32. A pharmaceutical preparation comprising a sterile pharmaceutical excipient and a compound represented by the general formula (I):

33. A method for treating or preventing basal cell carcinoma, comprising administering the pharmaceutical preparation of claim 32 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

34. A pharmaceutical preparation comprising a sterile pharmaceutical excipient and a compound represented by the general formula (II):

35. A method for treating or preventing basal cell carcinoma, comprising administering the pharmaceutical preparation of claim 34 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.