Regulators of the Endoplasmic Reticulum Proteostasis Network

Abstract

The invention provides compounds for activating the activating transcription factor 6 (ATF6) arm of the unfolded protein response (UPR), or activating the transcriptional targets of ATF6, in the endoplasmic reticulum of a cell, the compounds being of any of formulas (I) through (IX) as described herein. The compounds can be used for treatment of conditions involving gain-of-toxic-function and loss-of-function folding disorders including lysosomal storage diseases, antitrypsin-associated emphysema and similar diseases. These molecules are also expected to have disease-ameliorating effects in Alzheimer's disease and diabetes.

What is claimed is: 
     
         1 . A method of treating epilepsy, achromatopsia, antitrypsin associated liver cancer, antitrypsin associated lung disease, antitrypsin associated emphysema, retinitis pigmentosa associated with mutant rhodopsin aggregation, or ischemic-reperfusion injury in a patient afflicted therewith, comprising administering to the patient an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein Q is S, O, CH 2 , CHF, or CF 2 , 
         n=1, 2, 3, or 4, when Q is CH 2 , CHF, or CF 2 ; 
         n=1 when Q is S or O, and 
         V, W, X, Y and Z are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, or alkoxy; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the epilepsy is associated with mutant aminobutyric acid Type A GABA receptors. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) is any one of