Small molecule toll-like receptor (TLR) antagonists

Abstract

The invention provides methods and compositions useful for modulating signaling through Toll-like receptors. The methods involve contacting a TLR-expressing cell with a small molecule having a core structure including at least two rings. Certain of the compounds are 4-primary amino quinolines. Many of the compounds and methods are useful specifically for inhibiting immune stimulation involving at least one of TLR9, TLR8, TLR7, and TLR3. The methods may have use in the treatment of autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease, infection, sepsis, cancer, and immunodeficiency.

1 - 142 . (canceled)  
     
     
         143 . A compound having the structural formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X is aryl;  
 NR 1 R 2  is N-methyl-N′-piperazine;  
 Y is NH;  
 L is C 2 H 4 ;  
 R 3  and R 4  form a morpholino group;  
 R 5  and R 8  are each a hydrogen atom; and  
 R 6  and R 7  are each independently an alkoxy group,  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         144 . The compound of  claim 143 , wherein R 6  and R 7  are each methoxy, and pharmaceutically acceptable salts thereof.  
     
     
         145 . The compound of  claim 143 , wherein R 6  and R 7  are each methoxy.  
     
     
         146 . A method of inhibiting signaling by a Toll-like receptor (TLR), comprising 
 contacting a cell expressing a functional TLR with an effective amount of a composition comprising the compound of  claim 143 , to inhibit signaling by the TLR.    
     
     
         147 . The method of  claim 146 , wherein the TLR is TLR9.  
     
     
         148 . A method of inhibiting signaling by a Toll-like receptor (TLR), comprising 
 contacting a cell expressing a functional TLR with an effective amount of a composition comprising the compound of  claim 144 , to inhibit signaling by the TLR.    
     
     
         149 . The method of  claim 148 , wherein the TLR is TLR9.  
     
     
         150 . A method of inhibiting signaling by a Toll-like receptor (TLR), comprising 
 contacting a cell expressing a functional TLR with an effective amount of a composition comprising the compound of  claim 145 , to inhibit signaling by the TLR.    
     
     
         151 . The method of  claim 150 , wherein the TLR is TLR9.  
     
     
         152 . A method of treating an autoimmune disorder in a subject, comprising 
 administering to the subject an effective amount of a composition comprising the compound of claims  143 , to treat the autoimmune disorder.    
     
     
         153 . The method of  claim 152 , wherein the subject is a human.  
     
     
         154 . A method of treating an autoimmune disorder in a subject, comprising 
 administering to the subject an effective amount of a composition comprising the compound of claims  144 , to treat the autoimmune disorder.    
     
     
         155 . The method of  claim 154 , wherein the subject is a human.  
     
     
         156 . A method of treating an autoimmune disorder in a subject, comprising 
 administering to the subject an effective amount of a composition comprising the compound of claims  145 , to treat the autoimmune disorder.    
     
     
         157 . The method of  claim 156 , wherein the subject is a human.