Compounds and Compositions That Bind and Stabilize Transthyretin and Their Use for Inhibiting Transthyretin Amyloidosis and Protein-Protein Interactions

Abstract

Disclosed herein are compounds and compositions thereof which find use in increasing stability of proteins particularly proteins that tend to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of proteins and thereby decreasing aggregate formation by these proteins. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.

1 - 31 . (canceled) 
     
     
         32 . A compound of Formula (Ib) or (Ic) 
       
         
           
           
               
               
           
         
         wherein 
         X a , X b , and X c , are each independently selected from C(R 4 )(R 5 ), O, N—R 5  or S; wherein R 4  and R 5  are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkoxy, aryloxy, hydroxyl, a heterocyclic group, halogen, nitro, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; 
         R 1  and R 2 , when present, are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, alkoxy, aryloxy, hydroxyl, a heterocyclic group, halogen, nitro, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; 
         ring A is a 4- to 12-membered ring, in certain embodiments the 4- to 12-membered ring is an aromatic or heteroaromatic ring; 
         each Y is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkoxy, aryloxy, hydroxyl, a heterocyclic group, halogen, nitro, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, sulfonamide, sulfonyl fluoride, thioester, and cyano; and 
         c is a number from zero to 5; 
         or a pharmaceutically acceptable salt, ester, enol ether, enol ester, amide, acetal, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 
       
     
     
         33 . The compound of  claim 32 , wherein X a , X b , and X c  are each independently C(R 4 )(R 5 ). 
     
     
         34 . The compound of  claim 32 , wherein ring A is a phenyl ring. 
     
     
         35 . The compound of  claim 32 , wherein c is 2. 
     
     
         36 . The compound of  claim 32 , wherein each Y is independently selected from hydrogen, alkyl, halogen, and carboxyl. 
     
     
         37 . The compound of  claim 32 , wherein the compound is a compound of formula (Ib), and R 1  and R 2  are each independently alkyl. 
     
     
         38 . The compound of  claim 32 , wherein the compound is a compound of formula (Ic), and R 1  is hydrogen. 
     
     
         39 . A compound having the formula (VIIIa) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         40 . A compound having the formula (VIIIb) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . A pharmaceutical composition comprising the compound of  claim 32  and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient or a pharmaceutically acceptable adjuvant. 
     
     
         42 . A method of treating a transthyretin amyloid disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 32 . 
     
     
         43 . A kit comprising a unit dose of a compound of  claim 32 . 
     
     
         44 . A method of stabilizing transthyretin (TTR) in a tissue or biological fluid, the method comprising contacting the tissue or biological fluid with a compound of  claim 32 . 
     
     
         45 . A method of decreasing amyloid fibril formation in a tissue or biological fluid, the method comprising contacting the tissue or biological fluid with a compound of  claim 32 .