Small organic molecule regulators of cell proliferation

• US 20080194637A1
• Filed: 11/02/2007
• Published: 08/14/2008
• Est. Priority Date: 11/02/2006
• Status: Abandoned Application

• Current Assignee: Curis, Inc., Wyeth (Pfizer Inc.)
• Original Assignee: Curis, Inc., Wyeth (Pfizer Inc.)
• Inventors: Guicherit, Oivin M., Brunton, Shirley Ann, Haydar, Simon N., Kruse, Lawrence I., Springer, Dane
• Application Number:
  US11/982,708
• Publication Number:
  US 20080194637A1
• Time in Patent Office: Days
• US Class Current: 514/337
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention makes available methods and reagents for modulating proliferation or differentiation in a cell or tissue comprising contacting the cell with a compound. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal patched pathway or agonizing smoothened or hedgehog activity.

Claims

1. A compound represented by general Formula (V):

3. A composition comprising a compound of any one of claims 1-2 and a pharmaceutically acceptable excipient;

wherein the composition is optionally suitable for oral administration.

4. A method for

A) agonizing the hedgehog pathway in a cell, comprising contacting the cell with a compound of any one of claims 1-2 or a composition of claim 3;

wherein the method is optionally characterized by one or more of the following;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less;

the cell is contacted with the compound in vitro;

or

the cell is contacted with the compound in vivo;

or

B) modulating proliferation, differentiation, or survival of a cell, comprising contacting the cell with a compound of any one of claims 1-2 or a composition of claim 3;

wherein the method is optionally characterized by one or more of the following;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less;

the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less;

the cell is contacted with the compound in vitro;

or

the cell is contacted with the compound in vivo;

or

C) treating or preventing a condition of the central nervous system, comprising administering to a patient a compound of any one of claims 1-2 or a composition of claim 3;

wherein the condition is optionally Parkinson'"'"'s disease, Huntington'"'"'s disease, or ischemia;

or

D) treating or preventing cardiovascular disease, comprising administering a compound of any one of claims 1-2 or a composition of claim 3 to a patient in need thereof;

wherein the compound or composition is optionally released from a stent;

wherein the stent optionally releases the compound or composition over a period of at least about 4, 8, 12, 24, 48, or 72 hours, at least about 1, 2, 3, 4, or 5 days, at least about 1, 2, or 3 weeks, or at least about 1, 2, 3, 4, 5, or 6 months;

or

E) treating peripheral ischemia, comprising administering a compound of any one of claims 1-2 or a composition of claim 3 to a patient in need thereof;

or

F) promoting angiogenesis, comprising administering a compound of any one of claims 1-2 or a composition of claim 3;

or

G) treating tissues of a patient damaged by stroke, comprising administering a compound of any one of claims 1-2 or a composition of claim 3;

wherein the method is optionally characterized by one or more of the following;

the compound or composition is administered after the stroke;

the compound or composition is administered about 1, 5, 10, 30, or 60 minutes after the stroke;

the compound or composition is administered about 2, 4, 8, 16, 24, or 48 hours after the stroke;

or

the compound or composition is administered about 2, 4, or 8 days after the stroke.

2. A compound selected from: