INHIBITORS OF MICROBIALLY INDUCED AMYLOID
The present disclosure provides compounds useful for the prevention of amyloid formation and the treatment of amyloid related disorders, including synucleopathics such as Parkinson's Disease.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
L 1 is a bond or —N(R 5 )(C═O)—;
L 2 is —(C═O)— or —(C═O)O—;
G 1 is —N(R 5 ) 2 or R 6 ;
G 2 is —H, —N(R 5 ) 2 or —N(R 5 )(R 6 );
R 5 is independently, for each occurrence, —H or C 1-6 alkyl;
R 6 is aryl substituted with n instances of R 7 ;
R 7 is independently, for each occurrence, —F, —OH or —O(C 1-6 alkyl); and
n is 0, 1, 2, or 3;
provided that the compound does not have the structure:
2 . The compound of claim 1 , wherein Formula (I) is of Formula (I-a):
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
G 1 is R 6 ;
G 2 is —NH 2 or —N(R 5 )(R 6 );
R 5 is —H or —CH 3 ;
R 6 is phenyl substituted with n instances of R 7 ;
R 7 is independently, for each occurrence, —F, —OH or —OCH 3 ;
n is 0, 1, 2, or 3;
provided that:
(a) the compound comprises at least one instance of R 6 ; and/or
(b) the compound comprises at least three instances of R 7 .
4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is —CH 3 .
5 . The compound of claim 1 , wherein Formula (I) is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.
6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein G 1 is R 6 .
7 . The compound or pharmaceutically acceptable salt of claim 1 , wherein G 2 is —NH 2 .
8 . The compound or pharmaceutically acceptable salt of claim 1 , wherein G 2 is —N(R 5 )(R 6 ).
9 . The compound of claim 5 , wherein Formula (I-b) is of Formula (I-b-1) or Formula (I-b-2):
or a pharmaceutically acceptable salt thereof.
10 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each R 7 is independently selected from —OH and —OCH 3 .
11 . The compound or pharmaceutically acceptable salt of claim 1 , having 3-5 instances of R 7 .
12 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each R 6 is independently selected from:
wherein each R 6 is independently selected from:
13 - 14 . (canceled)
15 . The compound claim 1 , selected from:
and pharmaceutically acceptable salts thereof.
16 - 35 . (canceled)
36 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
37 - 43 . (canceled)
44 . A method for inhibiting amyloid formation in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
45 . A method for preventing or treating an amyloid disorder in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
46 . The method of claim 45 , wherein the amyloid disorder is a neurological disorder, intestinal dysbiosis, intestinal hyperpermeability, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis or Crohn's disease.
47 . The method of claim 45 , wherein the amyloid 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.
48 - 56 . (canceled)
57 . A method of disrupting and/or inhibiting the formation of amyloid aggregates comprising contacting amyloid or a precursor of amyloid with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
58 . A method of disrupting the formation of amyloid aggregates in a subject in need thereof, comprising:
administering to said subject a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
59 - 77 . (canceled)