Inhibitors of microbially induced amyloid

Abstract

The present disclosure provides compounds useful for the prevention of amyloid formation and the treatment of amyloid related disorders, including synucleopathies such as Parkinson's Disease.

1 - 77 . (canceled) 
     
     
         78 . A method for inhibiting amyloid formation, or amyloid aggregate formation, in a subject, comprising administering to the subject a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 L 1  is a bond; 
 L 2  is a bond, —CH 2 —, —(C═O)—, —(C═O)O—, or —NR 2 (C═O)—; 
 G 1  is —H or R 3 ; 
 G 2  is —H, —N(R 2 ) 2 , —N(R 2 )(R 3 ) or R 3 ; 
 R is —H or C 1-6  alkyl; 
 R 1  is —F, —OH, or —O(C 1-6  alkyl); 
 R 2  is independently, for each occurrence, —H or C 1-6  alkyl; 
 R 3  is aryl substituted with n instances of R 4 ; 
 R 4  is independently, for each occurrence, —F, —OH or —OCH 3 ; 
 n is, for each occurrence, 0, 1, 2, 3, or 4; and 
 m is 0, 1, 2, 3, or 4. 
 
     
     
         79 . The method of  claim 78 , wherein:
 L 1  is a bond;   L 2  is a bond, —CH 2 —, —(C═O)—, —(C═O)O—, or —NR 2 (C═O)—;   G 1  is —H or R 3 ;   G 2  is —N(R 2 )(R 3 ) or R 3 ;   R is H or —CH 3 ;   R 1  is —OH or —OCH 3 ;   R 2  is —H or —CH 3 ;   R 3  is phenyl substituted with m instances of R 4 ;   R 4  is independently, for each occurrence, —F, —OH or —OCH 3 ;   n is, for each occurrence, 0, 1, 2, 3, or 4; and   m is 0, 1, 2, 3, or 4.   
     
     
         80 . The method of  claim 78 , wherein Formula (II) is of Formula (II-a) or Formula (II-b): 
       
         
           
           
               
               
           
         
       
     
     
         81 . The method of  claim 80 , wherein Formula (II-a) is of Formula (II-a-1) or Formula (II-a-2): 
       
         
           
           
               
               
           
         
         and wherein Formula (II-b) is of Formula (II-b-1) or Formula (II-b-2): 
       
       
         
           
           
               
               
           
         
       
     
     
         82 . The method of  claim 78 , wherein the sum of all instances of m and n is 3-9. 
     
     
         83 . The method of  claim 78 , wherein each R 3  is independently selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . The method of  claim 78 , selected from: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         85 . The method of  claim 78 , wherein the subject is at risk of developing, or has been diagnosed with, an amyloid disorder. 
     
     
         86 . The method of  claim 85 , wherein the amyloid disorder is diagnosed by detecting the presence or level of intestinal bacterial amyloid aggregates. 
     
     
         87 . The method of  claim 86 , wherein the aggregates comprise a bacterial CsgA protein. 
     
     
         88 . The method of  claim 85 , wherein the amyloid disorder is a neurological disorder. 
     
     
         89 . The method of  claim 88 , wherein the neurological disorder is Parkinson's disease (PD), Lewy body dementia, multiple system atrophy, α-synucleinopathy, PD-associated constipation, PD-associated hyposmia, Huntington's Disease, Alexander's Disease, amyotrophic lateral sclerosis (ALS), or Alzheimer's Disease. 
     
     
         90 . The method of  claim 85 , wherein the amyloid disorder is intestinal dysbiosis, intestinal hyperpermeability, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis or Crohn's disease. 
     
     
         91 . The method of  claim 78 , wherein the subject suffers from gastrointestinal symptoms including one or more of dysphagia, reduced gut motility, gastroparesis, constipation (including chronic constipation and chronic idiopathic constipation), small intestine bacterial overgrowth (SIBO), diarrhea, abdominal pain and/or cramping, bloating, flatulence, hypersalivation (sialorrhea), anorectal dysfunction, dyssynergic defecation, and nausea. 
     
     
         92 . The method of  claim 78 , wherein the gastrointestinal symptoms are associated with Parkinson's Disease or Parkinsonism. 
     
     
         93 . The method of  claim 78 , wherein the amyloid aggregates comprise one or more mammalian proteins. 
     
     
         94 . The method of  claim 93 , wherein the mammalian proteins are selected from α-synuclein, tau, Beta amyloid from Amyloid precursor protein, Medin, Apolipoprotein AI, Atrial natriuretic factor, Beta amyloid, Cystatin, IAPP (Amylin), Beta-2 microglobulin, Transthyretin, PrP, Gelsolin, Lysozyme, Huntingtin, Keratoepithelin, Calcitonin, Prolactin, Serum amyloid A, SOD1, and Immunoglobulin light chain AL. 
     
     
         95 . The method of  claim 78 , wherein the amyloid aggregates comprise one or more bacterial or fungal proteins. 
     
     
         96 . The method of  claim 95 , wherein the bacterial protein is CsgA. 
     
     
         97 . The method of  claim 78 , wherein the amyloid aggregates are present within the gastrointestinal tract, cranial sinus, or nasal cavity of the subject.