Modulators of hedgehog signaling pathways, compositions and uses related thereto

• US 20050222087A1
• Filed: 04/22/2003
• Published: 10/06/2005
• Est. Priority Date: 04/22/2002
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chen, James L, Beachy, Philip A, Taipale, Anssi Jussi Nikolai
• Granted Patent: US 7,655,674 B2
• Time in Patent Office: Days
• US Class Current: 514/63
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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

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 state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity. Such methods and reagents may also inhibit the hedgehog pathway in normal cells, e.g., where normal levels of hedgehog signalling are unwanted.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula (I):

2. A composition of claim 1, wherein Ar represents a substituted or unsubstituted phenyl ring, X and X₁ represent N for all occurrences, R₁ represents alkyl, heteroaralkyl, or aralkyl, R₈ represents 0 substituents, and R₉ represents two methyl groups separately located on the two unsubstituted carbon atoms of the ring to which it is attached.

13. The composition of claim 1, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an IC₅₀ of 1 μ

M or less.

14. A method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with a composition of claim 1.

15. The method of claim 14, wherein the cell has a phenotype of ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function.

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

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

18. The method of claim 14, wherein the compound is administered to an animal as part of a therapeutic or cosmetic application.

19. The method of claim 18, 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 primitive gut, regulation of hematopoietic function, and regulation of skin and hair growth.

20. A method for inhibiting unwanted proliferation of a cell, comprising contacting the cell with a composition of claim 1.

21. The method of claim 20, wherein the cell is a cancer cell.

22. The method of claim 21, wherein the cell is a cancer cell from a cancer selected from medulloblastoma, rhabdomyosarcoma, endodermally or gut-derived cancers (including small cell lung cancer, esophageal cancer, gastric (stomach) cancer, biliary cancer, and pancreatic cancer), urogenital cancers (including prostate cancer and bladder cancer), ovarian cancer, and uterine cancer.

23. A method for treating or preventing a carcinoma, comprising administering a composition of claim 1 to a patient in an amount sufficient to inhibit progression of the carcinoma.

24. The method of claim 23, wherein the carcinoma is a basal cell carcinoma.

3. A pharmaceutical composition comprising a compound having the structure

4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula II:

5. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula III:

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula IV:

7. A composition of claim 6, wherein Ar represents a substituted or unsubstituted phenyl ring, and Har represents a substituted or unsubstituted 2-pyridyl ring.

8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula V:

9. A composition of claim 8, wherein R₅ represents a trihalomethyl group, Y represents NH2, and Ar represents an optionally further substituted 2-hydroxyphenyl substituent.

10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula VI:

11. A composition of claim 10, wherein Ar represents a substituted or unsubstituted phenyl ring, X represents N, X₁ represents CR, and R₉ is absent or represents 1-4 substituents selected from halogen, alkyl, cyano, and nitro.

12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula VII:

25. A method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with a compound that inhibits activation of the hedgehog pathway downstream of smoothened.