Nr4a1 ligands, pharmaceutical compositions, and related methods of use

Abstract

NR4A1 ligands, pharmaceutical compositions including the NR4A1 ligands, and related methods of use are described. Methods of treating a disease or condition in an individual treatable by modulation of NR4A1 activity, comprising administering to the individual a therapeutically effective amount of a compound or a pharmaceutical composition described herein.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein, 
         R 1 , R 2 , R 1′ , and R 2′  are each independently selected from the group consisting of hydrogen, a linear alkyl group containing one to about ten carbon atoms, and a branched alkyl group containing one to about ten carbon atoms; 
         R 3 , R 4 , R 5 , R 6 , R 3′ , R 4′ , R 5′ , and R 6′  are each independently selected from the group consisting of hydrogen, a halogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, an alkoxy group containing one to about ten carbon atoms, and a nitro group; 
         R 7  is selected from the group consisting of hydrogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, a cycloalkyl group containing one to about ten carbon atoms, and an aryl group; 
         R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from the group consisting of H, a halogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, an alkoxy group containing one to about ten carbon atoms, a haloalkyl group containing one to about ten carbon atoms, a nitro group, a hydroxyl group, and a haloalkoxy group containing one to about ten carbon atoms; 
         wherein at least one of R 8 , R 9 , R 10 , R 11 , and R 12  is OH, and 
         wherein when R 10  is OH at least one of R 8 , R 9 , R 11 , and R 12  is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein R 8  is OH. 
     
     
         3 . The compound of  claim 2 , wherein R 9 , R 10 , R 11 , and R 12  are each H. 
     
     
         4 . The composition of  claim 2 , wherein R 9 , R 10 , R 11 , and R 12  are independently selected from the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, C 6 H 5 , and CN. 
     
     
         5 . The compound of  claim 2 , wherein R 10  is OCH 3 . 
     
     
         6 . The compound of  claim 2 , wherein R 11  is selected from the group consisting of CH 3 , OCH 3 , and CF 3 . 
     
     
         7 . The compound of  claim 2 , wherein R 9  and R 11  are Br. 
     
     
         8 . The compound of  claim 2  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
         9 . The compound of  claim 1 , wherein R 9  is OH. 
     
     
         10 . The compound of  claim 9 , wherein R 8 , R 10 , R 11 , and R 12  are each H. 
     
     
         11 . The compound of  claim 9 , wherein R 9 , R 10 , R 11 , and R 12  are independently selected from the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, C 6 H 5 , and CN. 
     
     
         12 . The compound of  claim 9 , wherein R 8  is a halogen. 
     
     
         13 . The compound of  claim 9  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
         14 . The compound of  claim 1 , wherein R 10  is OH. 
     
     
         15 . The compound of  claim 14 , wherein R 8 , R 9 , R 11 , and R 12  are independently selected the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, C 6 H 5 , and CN. 
     
     
         16 . The compound of  claim 14 , wherein R 9  is a halogen and R 11  is selected from the group consisting of H, a halogen, and OCH 3 . 
     
     
         17 . The compound of  claim 14  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
         18 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a disease or condition in an individual treatable by modulation of Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) activity, comprising administering to the individual a therapeutically effective amount of a compound according to  claim 1 , or a salt thereof. 
     
     
         20 . The method of  claim 19 , wherein the disease or condition is selected from the group consisting of cancer, thrombosis, colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis immunosuppression disorder, arthritis, asthma, stroke, restenosis, rhinitis, diabetes mellitus, and osteoporosis. 
     
     
         21 . The method of  claim 20 , wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, colon cancer, rhabdomyosarcoma, and lung cancer. 
     
     
         22 . The method of  claim 19 , wherein modulation of NR4A1 activity induces down-regulation of a protein selected from the group consisting β1-integrin, TXNDC5, survivin, EFGR, PAX3-FOX01A, and combinations thereof. 
     
     
         23 . The method of  claim 19 , wherein modulation of NR4A1 activity induces up-regulation of a protein selected from the group consisting of SERPINB5, GADD45α, and combinations thereof. 
     
     
         24 . The method of  claim 20 , wherein the disease is diabetes mellitus and modulation of NR4A1 activity induces glucose uptake in the individual. 
     
     
         25 . The method of  claim 24 , wherein modulation of NR4A1 activity induces up-regulation GLUT-4 and Rab4 and phosphorylation of AMPK. 
     
     
         26 . The method of  claim 19 , wherein the administering comprises topical administration, oral administration, intravenous injection, intraperitoneal injection, intramuscular injection, intranasal administration, transdermal administration, rectal administration, or combinations thereof. 
     
     
         27 . A method of modulating NR4A1 activity in a cell, comprising administering to the cell a compound according to  claim 1 , or a salt thereof. 
     
     
         28 . The method of  claim 27 , wherein modulating NR4A1 activity in the cell comprises reducing the level of functional NR4A1 in the cell. 
     
     
         29 . The method of  claim 27 , wherein the cell is a cancer cell. 
     
     
         30 . The method of  claim 27 , wherein the cell is contacted with the compound or pharmaceutical composition in vitro. 
     
     
         31 . The method of  claim 27 , wherein the cell is contacted with the compound or pharmaceutical composition in vivo by administering an effective amount of the compound or pharmaceutical composition to a subject. 
     
     
         32 . The method of  claim 27 , wherein modulation of NR4A1 activity induces down-regulation of a protein selected from the group consisting β1-integrin, TXNDC5, survivin, EFGR, PAX3-FOX01A, and combinations thereof. 
     
     
         33 . The method of  claim 27 , wherein modulation of NR4A1 activity induces up-regulation of a protein selected from the group consisting of SERPINB5, GADD45α, and combinations thereof.