Inhibitors of hedgehog signaling pathways, compositions and uses related thereto

• US 7,291,626 B1
• Filed: 11/08/2000
• Issued: 11/06/2007
• Est. Priority Date: 04/09/1998
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Beachy, Philip A., Porter, Jeffrey A., Cooper, Michael K.
• Primary Examiner(s): Badio; Barbara P.
• Application Number:
  US09/708,964
• Time in Patent Office: 2,554 Days
• Field of Search: 514/278
• US Class Current: 514/278
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• 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 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• 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

Abstract

The present invention makes availables assays and reagents inhibiting paracrine and/or autocrine signals produced by a hedgehog protein or aberrant activation of a hedgehog signal transduction pathway, e.g., which involve the use of a steroidal alkaloid or other small molecule.

Claims

1. A method for inhibiting mitotic cell proliferation in an animal, wherein the mitotic cell proliferation is associated with a cancer, comprising administering to the animal a purified compound represented in the general formula (I), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:

3. The method of claim 1, wherein the compound is represented in Formula (Ia), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:

5. The method of any one of claims 1-2, wherein the compound is administered topically.

6. The method of any one of claims 1-2, wherein R₂ and R₃, independently for each occurrence, are —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈.

7. The method of any one of claims 1-2, wherein R₄, independently for each occurrence represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈.

8. The method of any one of claims 1-2, wherein R₆ is selected from hydrogen, alkyls, alkenyls, alkynyls, amines, imines, amides, carbonyls, carboxyls, carboxamides, ethers, thioethers, esters, or —

(CH₂)_m—

R₈.

9. The method of any one of claims 1-2, wherein R₇ and R′

₇, taken together with the carbon atom to which they are attached, form a perhydrofuro[3,2-b]pyridine.

10. The method of any one of claims 1-2, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

11. The method of any one of claims 1-2, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

12. The method of any one of claims 1-2, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

13. The method of any one of claims 1-2, wherein the cancer is a basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, or an epidermoidoma.

14. The method of claim 13, wherein the cancer is a basal cell carcinoma.

15. The method of claim 13, wherein the cancer is medulloblastoma.

16. The method of any one of claims 1-2, wherein the compound is jervine or cyclopamine.

17. The method of any one of claims 1-2, wherein the furo[3,2-b]piperidine ring system is substituted with one or more halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —

CF₃, or —

CN.

2. A method for inhibiting mitotic cell proliferation in an animal, wherein the mitotic cell proliferation is associated with a cancer, comprising administering to the animal a purified compound represented in the general formula (II), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:

4. The method of claim 2, wherein the compound is represented in Formula (IIa), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof: