Small organic molecule regulators of cell proliferation

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.

1 . A compound represented by general formula (V): 
       
         
           
           
               
               
           
         
         wherein, as valence and stability permit, 
         Z is a substituted or unsubstituted aryl or heteroaryl ring, provided that Z is not a substituted or unsubstituted pyridine N-oxide ring or a pyridine ring substituted with one or more halogens; 
         R a  is methyl; 
         R 1  is halogen, methoxy, or ethoxy; 
         R 2  is H; 
         Y 2  and Y 4  are, independently, H or fluoro; 
         Y 3  is H or fluoro; 
         wherein the two nitrogen atoms bonded to the cyclohexane ring depicted in Formula V are in a trans relationship; and 
         the compound is not one of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and 
         the compound is not one of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the compound is optionally characterized by one or more of the following: 
         R 1  is methoxy; 
         R 1  is fluoro; 
         R 1  is ethoxy; 
         at least one of Y 2  or Y 4  is F; 
         Y 2  and Y 4  are F; 
         Y 2  is F and Y 4  is H; 
         Z is a substituted or unsubstituted aryl ring; 
         Z is a substituted or unsubstituted phenyl ring; 
         Z is a substituted or unsubstituted heteroaryl ring; 
         Z is a substituted or unsubstituted pyridine, pyrimidine, pyrazine, pyridazine, triazine, tetrazine, pyrrole, pyrazole, or imidazole ring; 
         Z is a substituted or unsubstituted pyridine, pyrimidine, or pyrazine ring; 
         Z is a substituted or unsubstituted pyridine ring; 
         Z is a substituted or unsubstituted 4-pyridine ring; 
         Z is a substituted or unsubstituted 3-pyridine ring; 
         Z is a substituted or unsubstituted 2-pyridine ring; 
         Z is a substituted or unsubstituted 5-pyrimidine ring; 
         Z is a substituted or unsubstituted 2-pyrimidine ring; 
         Z is a substituted or unsubstituted 2-pyrazine ring; 
         Z is unsubstituted; 
         Z is substituted with one or more electron withdrawing groups; 
         Z is substituted with one or more groups selected from halogen, lower alkyl, lower alkenyl, —CN, azido, NR X R X ; —CO 2 OR X , —C(O)—NR X R X , —C(O)—R X , —NR X —C(O)—R X , —NR X SO 2 R X , —SR X , —S(O)R X , —SO 2 R X , —SO 2 NR X R X , —(C(R X ) 2 ) n —OR X , —(C(R X ) 2 ) n —, NR X R X , and —(C(R X ) 2 ) n —SO 2 R X ; wherein R X  is, independently for each occurrence, H or lower alkyl; and n is, independently for each occurrence, an integer from 0 to 2; 
         Z is substituted with one or more groups selected from halogen, —CN, azido, —CO 2 OR X , —C(O)—NR X R X , and —C(O)—R X ; 
         Z is substituted with fluoro; or 
         the compound is one of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient; wherein the composition is optionally suitable for oral or topical administration. 
     
     
         3 . A method for
 A) agonizing the hedgehog pathway in a cell, comprising contacting the cell with a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the compound agonizes hedgehog mediated signal transduction with an ED 50  of 1 mM or less; the compound agonizes hedgehog mediated signal transduction with an ED 50  of 1 μM or less; the compound agonizes hedgehog mediated signal transduction with an ED.sub.50 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  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the compound agonizes hedgehog mediated signal transduction with an ED 50  of 1 mM or less; the compound agonizes hedgehog mediated signal transduction with an ED 50  of 1 mu.m or less; the compound agonizes hedgehog mediated signal transduction with an ED 50  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  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the condition is Parkinson's disease, Huntington's disease, or ischemia; or the composition is suitable for oral administration; or   D) treating or preventing cardiovascular disease, comprising administering a compound of  claim 1  or a composition of  claim 2  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  claim 1  or a composition of  claim 2  to a patient in need thereof; or   F) promoting angiogenesis, comprising administering a compound of  claim 1  or a composition of  claim 2 ; or   G) treating tissues of a patient damaged by stroke, comprising administering a compound of  claim 1  or a composition of  claim 2 ; 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; or   H) growing or culturing cells in vitro, comprising contacting the cells with a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the cells are progenitor cells; the cells are neural progenitor cells; or the cells are neuronal cells; or   I) delivering cells to an anatomical site of a patient, comprising: culturing the cells, including contacting the cells with a compound of  claim 1  or a composition of  claim 2 ; and implanting the cells at the anatomical site of the patient; wherein the cells are optionally neuronal cells; or   J) promoting wound healing, comprising administering to a patient a compound of Any one of  claim 1  or a composition of  claim 2 ; or   K) inhibiting aging effects on skin, comprising administering to a patient a compound of  claim 1  or a composition of  claim 2 ; or   L) regulating skin or hair growth, comprising administering to a patient a compound of  claim 1  or a composition of  claim 2 ; or   M) promoting the formation and/or proliferation of hair follicles, comprising Administering a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the compound or composition is administered to a patient; or the method is an ex vivo method; or   N) increasing hair coverage at an anatomical site of a patient, comprising a) growing hair by ex vivo culture, formation, growth, differentiation, and/or expansion of hair follicles comprising contacting cells with a compound of  claim 1  or a composition of  claim 2 ; and b) implanting the grown hair at the anatomical site of the patient; or   O) inducing anagen in a telogenic hair follicle, comprising administering a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the compound or composition is administered to a patient; or the method is an ex vivo method; or   P) increasing the trichogenicity of hair follicle cells, comprising contacting the cells with a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the compound or composition is administered to a patient; or the method is an ex vivo method; or   Q) treating or preventing alopecia in a patient comprising administering a compound of  claim 1  or a composition of  claim 2 ; wherein the method is optionally characterized by one or more of the following: the alopecia is alopecia areata; or the alopecia is alopecia totalis; wherein in any of the methods described in sections L) to Q) above the patient optionally displays male or female pattern baldness; wherein in any of the methods described in sections J) to Q) above the compound or composition is optionally administered topically; wherein in any of the methods described in sections J) to Q) above the patient is optionally a human; wherein in any of the methods described in sections J) to Q) above the patient is optionally a non-human animal; wherein the patient is optionally a dog; or   R) treating or preventing amyotrophic lateral sclerosis (ALS), comprising administering a compound of  claim 1  or a composition of  claim 2 ; or   S) treating or preventing multiple sclerosis (MS), comprising administering a compound  claim 1  or a composition of  claim 2 ; or   T) treating or preventing Parkinson's disease or Huntington's disease, comprising administering a compound of  claim 1  or a composition of  claim 2 .