SMALL MOLECULE INHIBITORS OF BACTERIAL TOXINS
Described herein are compounds and compositions for use in treatment or prevention of an inflammatory bowel disease, gastrointestinal cancer, or a systemic bacterial infection in a subject in need thereof. The subject may be colonized by one or more pathogenic bacterial strains such as B. fragilis, E. faecalis , or C. perfringens . In certain aspects, the disclosure provides a method of diminishing the pathogenic effects of these bacterial strains by administering a compound that binds to and/or inhibits one or more toxins produced thereby.
1 . A compound of Formula IB:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is —NH—;
Y is —OH;
R 1 is alkyl, haloalkyl, -alkylene-OH, -alkylene-NH 2 , -alkylene-C(═O)NH 2 , heteroaralkyl, aryl, aralkyl, -alkylene-S-alkyl, -alkylene-S-haloalkyl, -alkylene-S-aralkyl, or -alkylene-S-heteroaralkyl; wherein R 1 is optionally substituted with one or more groups selected from —OH, halogen, —CHF 2 , —CH 2 F, or —CF 3 ;
R 2 is H, —(CH 2 ) n -aryl, —CH 2 -alkyl, —CH(Me)-alkyl, —CH 2 -heterocyclyl, —(CH 2 ) n -heteroaryl, or —CH 2 -haloalkyl;
R 3 is —OH;
R 3a is H or halogen; and
n is an integer from 1-3.
2 . The compound of claim 1 , wherein the compound of Formula IB has the structure of Formula IB-1:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 or 2 , wherein R 1 is —C 1 -C 6 alkyl, —C 1 -C 6 alkyl-OH, —(C 1 -C 3 alkylene)-S—(C 1 -C 3 alkyl), —(C 1 -C 3 alkylene)-S—(C 1 -C 3 haloalkyl), —(C 1 -C 3 alkylene)-SCH 2 -heteroaryl, —CH 2 -phenyl, —CH 2 -heteroaryl, or —CH 2 C(═O)NH 2 , wherein phenyl is optionally substituted with one or more groups selected from —OH, —OMe, halogen, —CHF 2 , —CH 2 F, or —CF 3 .
4 . The compound of claim 1 or 2 , wherein R 1 is —CH 2 CH(CH 3 ) 2 , —CH(OH)CH 3 , —CH 2 CH 2 SCH 3 ,
—CH 2 -phenyl, —CH 2 -(3-indolyl), —CH 2 -(4-imidazolyl), —CH 2 C(═O)NH 2 ,
—CH(CH 3 )SCH 2 CH 3 , —CH(CH 3 )SCH 2 -(3-pyridyl), —CH(CH 3 )SCH 2 -(4-pyridyl), or —CH(CH 3 )SCH 2 CF 3 .
5 . The compound of claim 1 or 2 , wherein R 1 is alkyl, haloalkyl, -alkylene-OH, alkylene-O-alkyl, -alkylene-S-alkyl, heteroaralkyl, aryl, or aralkyl.
6 . The compound of claim 1 or 2 , wherein R 1 is alkyl, -alkylene-OH, alkylene-O-alkyl, heteroaralkyl, aryl, or aralkyl.
7 . The compound of claim 1 or 2 , wherein R 1 is alkyl, aryl, -alkylene-OH, alkylene-O-alkyl.
8 . The compound of claim 1 or 2 , wherein R 1 is alkyl or aryl.
9 . The compound of claim 1 or 2 , wherein R 1 is alkyl.
10 . The compound of any one of claims 5 - 9 , wherein the alkyl is a C 2-6 alkyl.
11 . The compound of any one of claims 5 - 10 , wherein the alkyl is ethyl or isobutyl.
12 . The compound of any one of claims 5 - 10 , wherein the alkyl is ethyl.
13 . The compound of any one of claims 5 - 8 , wherein the aryl is a C 6-12 aryl.
14 . The compound of claim 13 , wherein the C 6-12 aryl is phenyl.
15 . The compound of claim 14 , wherein the phenyl is substituted with one or more halogens.
16 . The compound of claim 13 or 14 , wherein the phenyl is 4-fluorophenyl.
17 . The compound of any one of claims 5 - 7 , wherein the alkylene is a C 1-3 alkylene.
18 . The compound of any one of claims 5 - 7 , wherein the alkylene is a methylene.
19 . The compound of any one of claims 1 - 18 , wherein R 2 is —CH 2 -alkyl, —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl.
20 . The compound of any one of claims 1 - 19 , wherein R 2 is —(CH 2 ) n -heteroaryl.
21 . The compound of claim 19 or 20 , wherein the heteroaryl is a 5- to 14-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, or S.
22 . The compound of claim 20 or 21 , wherein the heteroaryl is pyridyl, thiophenyl, thiazoyl, oxazolyl, or indolyl.
23 . The compound of any one of claims 20 - 22 , wherein the heteroaryl is pyridyl or indolyl
24 . The compound of one of claims 20 - 23 , wherein the heteroaryl is 3-pyridyl or 5-indolyl.
25 . The compound of any one of claims 1 - 24 , wherein n is 1 or 2.
26 . A compound of Formula V:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is —NH—;
Y is —OH—;
R 2 is —(CH 2 ) n -aryl, —CH 2 -alkyl, —CH(Me)-alkyl, —(CH 2 ) n -heteroaryl, or —CH 2 -haloalkyl; and
R 3 is H, alkyl, -alkylene-NR 5 R 6 , haloalkyl, aryl, aralkyl, or heteroaryl, each of which is optionally substituted;
R 5 is H, alkyl, aralkyl, heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, or —C(O)aralkyl;
R 6 is H, alkyl, or aryl; and
n is an integer from 1-3.
27 . The compound of claim 26 , wherein R 2 is —CH 2 alkyl.
28 . The compound of claim 26 or 27 , wherein R 2 is —CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 OCH 3 , or —CH 2 CHF 2 .
29 . The compound of any one of claims 26 - 28 , wherein R 2 is —CH 2 CH(CH 3 ) 2 .
30 . The compound of any one of claim 26 , wherein R 2 is —CH 2 -aryl, —CH 2 -alkyl, -or —CH 2 -heteroaryl.
31 . The compound of claim 26 or 30 , wherein R 2 is —CH 2 -Ph, —CH 2 —CH(CH 3 ) 2 , -or —CH 2 -(3-pyridyl).
32 . The compound of any one of claims 26 - 31 , wherein R 3 is —OH, alkoxy, —O— haloalkyl, —O-aralkyl, —O-heteroaralkyl, —O-alkylene-NR 5 R 6 , alkyl or —N(H)C(O)-alkylene-NR 5 R 6 , wherein the alkylene is optionally substituted with F, oxo, alkyl, fluoroalkyl, aryl, —CH 2 -aryl, or —CH 2 -heteroaryl.
33 . The compound of any one of claims 26 - 32 , wherein R 3 is —OH, alkoxy, or —O-alkylene-NR 5 R 6 .
34 . The compound of any one of claims 26 - 33 , wherein the alkoxy is —OCH 3 .
35 . The compound of any one of claims 26 - 35 , wherein the alkylene is a C 1-3 alkylene.
36 . The compound of any one of claims 26 - 35 , wherein the alkylene is a methylene or ethylene.
37 . The compound of claim 36 , wherein the —O-alkylene-NR 5 R 6 is —O—CH 2 —C(O)—NR 5 R 6 .
38 . The compound of any one of claims 26 - 37 , wherein R 5 is H or aralkyl or heteroaralkyl.
39 . The compound of claim 26 - 38 , wherein the aralkyl is —CH 2 aryl.
40 . The compound of claim 26 - 38 , wherein the aralkyl is —CH 2 Ph.
41 . The compound of claim 40 , wherein the phenyl is optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, thioalkyl, aryl, heteroaryl or combinations thereof.
42 . The compound of any one of claims 38 - 41 , wherein aralkyl is selected from the group consisting of:
43 . The compound of any one of claims 38 - 42 , wherein the aralkyl is
44 . The compound of any one of claims 38 - 43 , wherein the aralkyl is
45 . The compound of any one of claims 38 - 44 , wherein the heteroaralkyl is —CH 2 pyridyl or —CH 2 thiophenyl.
46 . The compound of any one of claims 38 - 45 , wherein the heteroaralkyl is
47 . The compound of any one of claims 26 - 46 , wherein R 6 is H or alkyl.
48 . The compound of claim 47 , wherein the alkyl is a C 1-5 alkyl.
49 . The compound of any one of claims 26 - 48 , wherein n is 1 or 2.
50 . The compound of any one of claims 26 - 48 , wherein n is 1.
51 . The compound of claim 26 , wherein the compound of Formula V has a structure according to:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
R 2 is alkyl, —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl;
R 5 is H, aralkyl or heteroaralkyl;
R 6 is H, alkyl, or aryl; and
n is an integer from 0-3.
52 . The compound of claim 51 , wherein R 2 is a C 1-5 alkyl, —CH 2 Ph or —CH 2 pyridyl.
53 . The compound of claim 51 or 52 , wherein R 2 is C 1-5 alkyl.
54 . The compound of any one of claims 51 - 53 , wherein R 2 is —CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 OCH 3 , or —CH 2 CHF 2 .
55 . The compound of any one of claim 51 , wherein R 5 is —CH 2 aryl or —CH 2 heteroaryl.
56 . The compound of claim 55 , wherein the —CH 2 aryl is selected from the group consisting of:
57 . The compound of claim 55 or 56 , wherein the —CH 2 aryl is
58 . The compound of any one of claims 55 - 57 , wherein the —CH 2 aryl is
59 . The compound of any one of claims 55 - 58 , wherein the —CH 2 heteroaryl is —CH 2 pyridyl or —CH 2 thiophenyl.
60 . The compound of any one of claims 55 - 59 , wherein the —CH 2 heteroaryl is
61 . The compound of any one of claims 51 - 60 , wherein R 6 is H.
62 . The compound of any one of claims 51 - 61 , wherein n is 1 or 2.
63 . The compound of claim 1 , wherein the compound of Formula I has a structure according to:
64 . The compound of claim 1 , wherein the compound of Formula I has a structure according to:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
65 . The compound of claim 29 , wherein the compound has a structure according to:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
66 . A compound of Formula A:
wherein:
R 1 is H or Me;
R 3 is Me or t-Bu; and
R 4 is H, Me, or Et.
67 . A Compound of Formula B:
wherein:
R 1 is H or Me;
R 2 is Ph, 3-Pyr, —CH 2 Ph, or —CH 2-3 -Pyr;
R 3 is Me or t-Bu; and
R 4 is H, Me, or Et.
68 . A pharmaceutical composition comprising a compound of any one of claims 1 - 65 and a pharmaceutically acceptable carrier or excipient.
69 . A method of treating inflammatory bowel disease in a subject in need thereof, the method comprising, administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 65 .
70 . The method of claim 69 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
71 . A method of treating gastrointestinal (GI) cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 65 .
72 . The method of claim 71 , wherein the GI cancer is esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, stomach cancer, cancer of the small intestine, colorectal cancer, or anal cancer.
73 . A method of treating a systemic bacterial infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 65 .
74 . The method of claim 73 , wherein the systemic bacterial infection is endocarditis or a urinary tract infection.
75 . The method of any one of claims 69 - 74 , wherein the subject is colonized by one or more pathogenic bacterial strain.
76 . The method of claim 75 , wherein the pathogenic bacterial strain is B. fragilis, E. faecalis , and/or C. perfringens.
77 . The method of claim 75 or 76 , wherein the pathogenic bacterial strain is a strain of B. fragilis expressing the BFT toxin, a strain of E. faecalis expressing the gelatinase GelE, or a strain of C. perfringens expressing the collagenase ColA.
78 . The method of any one of claims 69 - 77 , wherein the compound binds to and/or inhibits one or more of B. fragilis toxin (BFT), collagenase A (ColA), and gelatinase E (GelE).
79 . The method of claim 78 , wherein the BFT comprises the amino acid sequence of any one of SEQ ID NO: 2-4.
80 . The method of claim 78 , wherein the BFT comprises an amino acid sequence that is at least 98% identical to any one of SEQ ID NO: 2-4.
81 . The method of claim 78 , wherein the ColA comprises the amino acid sequence of SEQ ID NO: 8.
82 . The method of claim 78 , wherein the ColA comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 8.
83 . The method of claim 79 , wherein the GelE comprises the amino acid sequence of SEQ ID NO: 6.
84 . The method of claim 80 , wherein the GelE comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 6.
85 . The method of any one of claims 77 - 84 , wherein the compound binds to BFT, ColA, and/or GelE with an inhibition constant in the range of about 10 −5 to about 10 −13 M.
86 . The method of any one of claims 77 - 84 , wherein the compound has an IC50 in the range of about 1 μM to about 500 μM.
87 . The method of claim 86 , wherein the IC50 is determined by measuring cleavage of a FRET-based peptide substrate.
88 . The method of claim 86 , wherein the FRET-based peptide substrate has a sequence of SEQ ID NO: 10.
89 . The method of any one of the claims 77 - 89 , wherein administering the compound reduces and/or eliminates the activity of at least one of BFT, ColA and/or GelE.
90 . The method of any one of claims 69 - 89 , wherein the subject is a mammal.
91 . The method of any one of claims 69 - 90 , wherein the subject is a human.
92 . The method of claim 91 , wherein the subject is male.
93 . The method of claim 91 , wherein the subject is female.
94 . The method of any one of claims 69 - 93 , wherein the compound is administered intravenously to the subject.
95 . The method of any one of claims 69 - 93 , wherein the compound is administered orally to the subject.
96 . The method of claim 95 , wherein the compound is administered in a tablet or a capsule.
97 . The method of claim 96 , wherein the tablet or capsule comprises a pharmaceutically acceptable carrier or excipient.
98 . The method of any one of claims 69 - 95 , wherein the compound is administered as a liquid formulation.
99 . The method of claim 98 , wherein the liquid formulation comprises a pharmaceutically acceptable carrier or excipient.
100 . The method of any one of claims 69 - 99 , wherein the compound is administered once per day, once per week, or multiple times per day or week.
101 . The method of any one of claims 69 - 100 , wherein a dose of the compound administered to the subject is from about 0.001 to about 1000 mg/kg of body weight per day.