G protein-coupled receptor (gpcr) modulation by imipridones

Abstract

Imipridones has been found to selectively modulate Class A G protein-coupled receptors (GPCRs), such as the D2-like subfamily of dopamine receptors, and to be useful for the treatment of conditions and disorders in need of such modulation, such as cancers, psychiatric disorders, and bacterial infections. In addition, methods of identifying whether a subject having these condition, is likely to be responsive to a treatment regimen, such as administration of an imipridone, are provided. Furthermore, methods of assessing the effectiveness of a treatment regimen, such as administration of an imipridone, monitoring, or providing a prognosis for a subject with these condition are also provided.

1 .- 142 . (canceled) 
     
     
         143 . A method for treating a central nervous system cancer in a subject in need thereof, comprising administering a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein the central nervous system cancer is susceptible to modulation by one or more of a Dopamine Receptor (DR) and a G Protein Coupled Receptor (GPCR). 
     
     
         144 . The method of  claim 143 , wherein the cancer is meningioma, ependymoma, glioma, neuroblastoma or diffuse intrinsic pontine glioma. 
     
     
         145 . The method of  claim 143 , wherein the compound is an antagonist of one or more of the receptors. 
     
     
         146 . The method of  claim 143 , wherein the subject is a human. 
     
     
         147 . The method of  claim 143 , wherein the pharmaceutically acceptable salt is a di-hydrochloride salt. 
     
     
         148 . A method for treating a central nervous system cancer in a subject in need thereof, comprising administering a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein the central nervous system cancer has a histone H3 mutation. 
     
     
         149 . The method of  claim 148 , wherein the cancer is meningioma, ependymoma, glioma, neuroblastoma or diffuse intrinsic pontine glioma. 
     
     
         150 . The method of  claim 148 , wherein the cancer has an epigentically silenced unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene. 
     
     
         151 . The method of  claim 148 , wherein the subject is a human. 
     
     
         152 . The method of  claim 148 , wherein the pharmaceutically acceptable salt is a di-hydrochloride salt. 
     
     
         153 . A method for treating a central nervous system cancer in a subject in need thereof, comprising administering a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein the central nervous system cancer has a epigentically silenced unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene. 
     
     
         154 . The method of  claim 153 , wherein the cancer is meningioma, ependymoma, glioma, neuroblastoma or diffuse intrinsic pontine glioma. 
     
     
         155 . The method of  claim 153 , wherein the cancer has a histone H3 mutation. 
     
     
         156 . The method of  claim 153 , wherein the subject is a human. 
     
     
         157 . The method of  claim 153 , wherein the pharmaceutically acceptable salt is a di-hydrochloride salt.