Glucocorticoid inhibitors for treatment of prostate cancer

Abstract

The present invention encompasses the recognition that reproducible and detectable changes in the level and or activity of Glucorticoid Receptor (GR) are associated with incidence and/or risk of Castration Resistant Prostrate Cancer (CRPC) and/or doubly resistant prostrate cancer, especially in individuals having prostrate cancer and on antiandrogen therapy, and provides for the use of GR inhibitors to treat and/or reduce risk of CRPC and/or doubly resistant prostrate cancer. In some embodiments, GR inhibitors also have Androgen Receptors (AR) inhibitory activity and or administered in conjunction with AR Inhibitors. The present invention also provides technologies for identification and/or characterization of agents to treat and/or reduce risk of CRPC and/or doubly resistant prostrate cancer; in some embodiments such agents alter level and/or activity of a GR. In some embodiments, provided agents show effects on a GR's activity of regulating transcription of one or more target genes. The present invention also provides systems for using such agents, for example to treat and/or reduce risk of CRPC and/or doubly resistant prostrate cancer.

1 - 195 . (canceled) 
     
     
         196 . A compound having the structure of formula I or III: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is —OR; 
 R is optionally substituted phenyl; 
 R 2  is optionally substituted unsaturated C 2-6  aliphatic; 
 R s  is —H, —OH, —NH 2 , —CH 3 , —Br, —Cl, —F, —I, or O—C 1-6 alkyl; 
 m is an integer between 1-8; and 
 n is 1, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         197 . The compound of  claim 196 , wherein R 2  is selected from the group consisting of ethyn-1-yl, 1-propyn-1-yl, 1-butyn-1-yl, ethen-1-yl, 1-propen-1-yl, and 1-buten-1-yl. 
     
     
         198 . The compound of  claim 196 , wherein R 2  is 1-propyn-1-yl. 
     
     
         199 . The compound of  claim 196 , wherein the compound has the structure of formula II-a or formula III-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         200 . The compound of  claim 196 , wherein the compound has the structure of formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         201 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         202 . A pharmaceutical composition comprising a compound of  claim 196 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.