Modulators of Hedgehog Signaling Pathways, Compositions and Uses Related Thereto

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting form 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.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula (I): 
     
       
         
         
             
             
         
       
       wherein, as valence and stability permit, 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring; 
       X represents, independently for each occurrence, N or CR′; 
       X 1  represents, independently for each occurrence, N or CR″; 
       R′ represents, independently for each occurrence, H, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxyl, silyloxy, amino, alkylamino, nitro, cyano, thiol, amino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, or carbonate; 
       R″ represents, independently for each occurrence, H, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxyl, silyloxy, amino, alkylamino, nitro, cyano, thiol, amino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, or carbonate; 
       R 1  represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; 
       R 8  represents from 0-4 substituents on the ring to which it is attached, independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, cyano, thiol, amino, alkylamino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, and carbonate; and 
       R 9  represents from 0-4 substituents on the ring to which it is attached, independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxyl, silyloxy, amino, nitro, cyano, thiol, amino, alkylamino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, and carbonate, 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . A composition of  claim 1 , wherein Ar represents a substituted or unsubstituted phenyl ring, X and X 1  represent N for all occurrences, R 1  represents alkyl, heteroaralkyl, or aralkyl, R 8  represents 0 substituents, and R 9  represents two methyl groups separately located on the two unsubstituted carbon atoms of the ring to which it is attached. 
   
   
       3 . A pharmaceutical composition comprising a compound having the structure 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       4 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula II: 
     
       
         
         
             
             
         
       
       wherein, as valence and stability permit, 
       A represents a pyridyl or dihydropyridyl ring; 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring; and 
       R 9  represents from 0-4 substituents on the ring to which it is attached, independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxyl, silyloxy, amino, nitro, cyano, thiol, amino, alkylamino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, and carbonate, or a pharmaceutically acceptable salt thereof. 
     
   
   
       5 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula III: 
     
       
         
         
             
             
         
       
       wherein, independently for each occurrence, 
       A represents a pyridyl or dihydropyridyl ring; 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring; and 
       R 2  represents a thioether, preferably substituted with an amido, ester, carboxyl, or acyl; 
       R 3  represents H, alkyl, alkenyl, alkynyl, or cycloalkyl; and 
       R 4  represents a substituent selected from H, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxyl, silyloxy, amino, nitro, cyano, thiol, amino, alkylamino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, anhydride, silyl, thioether, alkylsulfonyl, arylsulfonyl, selenoether, acyl, aldehyde, ester, carbamate, and carbonate, or a pharmaceutically acceptable salt thereof. 
     
   
   
       6 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula IV: 
     
       
         
         
             
             
         
       
       wherein, as valence and stability permit, 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring; 
       W represents C═O, C═S, or SO 2 ; 
       Har represents a substituted or unsubstituted heteroaryl ring; 
       Ht represents OR or NR′″ 2 ; 
       R represents H or lower alkyl; and 
       R′″ represents H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or a pharmaceutically acceptable salt thereof. 
     
   
   
       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: 
     
       
         
         
             
             
         
       
       wherein, as valence and stability permit, 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring, preferably a substituted or unsubstituted phenyl ring, such as an ortho-hydroxyphenyl group optionally substituted with one or more halogen, hydroxy, alkoxy, amino, alkylamino, alkyl, thiol, alkylthio, ester, amido, carboxyl, nitro, or cyano substituents; 
       Y represents OH or NR 2 ; 
       Z represents O or S; 
       R represents H or lower alkyl; and 
       R 5  represents substituted or unsubstituted lower alkyl, 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       9 . A composition of  claim 8 , wherein R 5  represents a trihalomethyl group, Y represents NH 2 , 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 VII: 
     
       
         
         
             
             
         
       
       wherein, as valence and stability permit, 
       X and Z, independently, represent —N(R 7 )—, —O—, —S—, —(R 7 )N—N(R 7 )—, —ON(R 7 )—, or a direct bond; 
       Y represents —C(═O)—, —C(═S)—, —C(═NR 7 )—, SO 2 , or SO; 
       A represents O, S, or NR 7 ; 
       G represents a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring fused to the ring to which it is attached; 
       Ar represents a substituted or unsubstituted aryl or heteroaryl ring; 
       R 1  represents H or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl, including polycyclic groups; 
       R 2  represents from 0-4 substituents on the ring to which it is attached, such as halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl group, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, J-R 8 , J-OH, J-lower alkyl, Mower alkenyl, J-R 8 , J-SH, J-NH 2 , protected forms of the above, or any two R 2 , when occurring more than once in a cyclic or polycyclic structure, can be taken together form a 4- to 8-membered cycloalkyl, aryl, or heteroaryl; 
       R 7 , independently for each occurrence, represents H or substituted or unsubstituted lower alkyl, J-cycloalkyl, J-heterocyclyl, J-aryl, or J-heteroaryl; 
       R 8 , independently for each occurrence, represents H or substituted or unsubstituted lower alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and 
       J represents, independently for each occurrence, a chain having from 0-8 units selected from CK 2 , NK, O, and S, wherein K represents, independently for each occurrence, H or lower alkyl. 
     
   
   
       11 . 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 IC 50  of 1 μM or less. 
   
   
       12 . A method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with a composition of  claim 1 . 
   
   
       13 . The method of  claim 12 , wherein the cell has a phenotype of ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function. 
   
   
       14 . The method of  claim 12 , wherein the cell is contacted with the hedgehog antagonist in vivo. 
   
   
       15 . The method of  claim 12 , wherein the cell is contacted with the hedgehog antagonist in vitro, 
   
   
       16 . The method of  claim 12 , wherein the compound is administered to an animal as part of a therapeutic or cosmetic application. 
   
   
       17 . The method of  claim 16 , 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. 
   
   
       18 . A method for inhibiting unwanted proliferation of a cell, comprising contacting the cell with a composition of  claim 1 . 
   
   
       19 . The method of  claim 18 , wherein the cell is a cancer cell. 
   
   
       20 . The method of  claim 19 , 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. 
   
   
       21 . 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. 
   
   
       22 . The method of  claim 21 , wherein the carcinoma is a basal cell carcinoma. 
   
   
       23 . 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.