Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 6,545,005 B1
• Filed: 09/15/2000
• Issued: 04/08/2003
• Est. Priority Date: 09/16/1999
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curtis and Company
• Inventors: Rubin, Lee D., Price, Stephen, Guicherit, Oivin M., Boyd, Edward Andrew, Baxter, Anthony David
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US09/663,835
• Time in Patent Office: 935 Days
• Field of Search: 514/266.3, 514/252.16, 514/252.17, 544/287, 544/290
• US Class Current: 514/266.3
• 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 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 401/12 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 by contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize hedgehog activity.

Claims

1. A method for inhibiting signaling via a hedgehog pathway in a cell comprising contacting the cell with a hedgehog antagonist, wherein the hedgehog antagonist is an organic molecule represented in the general formula (II):

wherein, as valence permits,

R₁ and R₂, independently for each occurrence, represent H, lower alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);

L, independently for each occurrence, is absent or represents —

(CH₂)_n-alkyl, —

(CH₂)_nO(CH₂)_p—

, —

(CH₂)_nNR₂(CH₂)_p—

, —

(CH₂)_nS(CH₂)_p—

, —

(CH₂)_nalkenyl(CH₂)_p—

, —

(CH₂)_nalkynyl(CH₂)_p—

, —

O(CH₂)_n—

, —

NR₂(CH₂)_n—

, or —

S(CH₂)_n—

;

X is selected from —

N(R₈)—

, —

O—

, —

S—

, —

Se—

, —

N═

N—

, —

ON═

CH—

, —

(R₈)N—

N(R₈)—

, —

ON(R₈)—

, a heterocycle, or a direct bond between L and Y;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, —

S(O₂)—

, —

S(O)—

, —

C(═

NCN)—

, —

P(═

O)(OR₂)—

, a heteroaromatic group, or a direct bond between X and Z;

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, —

Se—

, —

N═

N—

, —

ON═

CH—

, —

R₈N—

NR₈—

, —

ONR₈—

, a heterocycle, or a direct bond between Y and L;

R₈, independently for each occurrence, represents H, lower alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted), or two R₈ taken together form a 4- to 8-membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;

W represents a substituted or unsubsituted aryl or heteroaryl ring fused to the pyrimidone ring;

p represents, independently for each occurrence, an integer from 0 to 10; and

n, individually for each occurrence, represents an integer from 0 to 10.

2. The method of claim 1, wherein R₁ represents a substituted or unsubstituted aryl or heteroaryl group.

3. The method of claim 1, wherein X—

Y—

Z taken together represents a urea or an amide.

4. The method of claim 1, wherein W is a substituted or unsubstituted benzene ring.

5. The method of claim 1, wherein X represents a diazacarbocycle.

6. The method of claim 1, wherein R₂ represents a substituted or unsubstituted aryl or heteroaryl group.

7. The method of claim 1, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

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

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

9. The method of claim 1, wherein at least one of X and Z is present.

10. The method of claim 1, wherein Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

11. The method of claim 1, wherein the hedgehog antagonist inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

12. The method of claim 1, wherein the hedgehog antagonist inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

13. The method of claim 1, wherein the hedgehog antagonist inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

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

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

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

17. The method of claim 16, 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.

18. The method of claim 1, wherein W represents a substituted or unsubstituted heteroaryl ring fused to the pyrimidone ring.

19. The method of claim 1, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

20. The method of claim 8, wherein W is a substituted or unsubstituted benzene ring.

21. The method of claim 20, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

22. The method of claim 8, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

24. The method of claim 8, wherein W represents a substituted or unsubstituted heteroaryl ring fused to the pyrimidone ring.

25. The method of claim 4, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

26. The method of claim 18, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

27. The method of claim 1, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

28. The method of claim 27, wherein W represents a substituted or unsubstituted heteroaryl ring fused to the pyrimidone ring.

29. The method of claim 27, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

30. The method of claim 27, wherein W is a substituted or unsubstituted benzene ring.

31. The method of claim 27, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

32. The method of claim 28, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

33. The method of claim 29, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

34. The method of claim 30, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

35. The method of claim 34, wherein

R₂ represents a substituted or unsubstituted aryl or heteroaryl group;

R₈, independently for each occurrence, is selected from H and lower alkyl;

p, individually for each occurrence, represents an integer in the range of 0 to 3; and

n, individually for each occurrence, represents an integer in the range of 0 to 5.

23. The method of claim 23, wherein W represents a substituted or unsubstituted heteroaryl ring fused to the pyrimidone ring.