Small-molecule botulinum toxin inhibitors
This disclosure relates to materials and methods for inhibiting Botulinum neurotoxin, and more particularly to materials and methods for inhibiting the zinc endopeptidase of Botulinum neurotoxin serotypes A, D and/or E (BoNTA, BoNTD and/or BoNTE).
1. A composition comprising a compound of Formula (IIA):
or a pharmaceutically acceptable salt or derivative thereof, wherein:
R 1 is chosen from NH 2 , aryl, and heteroaryl;
R 2 is chosen from NR 2a R 2b ;
R 2a and R 2b are chosen from (CH 2 ) m NH 2 ;
m is an integer from 4 to 12;
R 3 is chosen from thiol, imidazole, sulfonamide, COOH, and CONHOH;
R 4 and R 5 are independently chosen from aryl and heteroaryl;
R 6 is chosen from H, OH, CH 2 OH, NH 2 , aryl and heteroaryl;
U and X are independently (CH 2 ) m1 V(CH 2 ) m2 ;
V is chosen from C, C(OH), 0, S, and NH, or is absent;
m1 is an integer from 0 to 2;
m2 is an integer from 0 to 2;
W is chosen from 0 and S, or is absent;
Y is chosen from CO(CH 2 ) m3 , (CH 2 ) m3 , and CONH(CH 2 ) m3 ;
m3 is an integer from 1 to 10; and
all non-hydrogen atoms in the pyrrole ring can be substituted by N, S, or O provided the substitution maintain aromaticity.
2. The composition of claim 1 , wherein the compound of Formula (II-A) is chosen from:
or a pharmaceutically acceptable salt or derivative thereof, wherein:
R 6 is chosen from H, OH, CH 2 OH, and NH 2 ;
m is an integer from 3 to 10;
n is an integer from 5 to 10;
X is chosen from (CH 2 ) m1 V 1 (CH 2 ) m2 V 2 (CH 2 ) m3 ;
V 1 and V 2 are independently chosen from C, C(OH), O, S, and NH, or are absent;
m1 is an integer from 0 to 4;
m2 is an integer from 0 to 4; and
m3 is an integer from 0 to 4.
3. The composition of claim 1 , wherein the compound of Formula (II-A) is chosen from:
or a pharmaceutically acceptable salt or derivative thereof.
4. A kit comprising a composition according to claim 1 .
5. The kit of claim 4 , wherein the composition is in the form of an injectable composition.
6. A pharmaceutical composition comprising a composition of claim 1 and a pharmaceutically acceptable carrier, excipient, or adjuvant.
7. The compound of claim 1 , wherein the compound of Formula (IIA) is:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein R 3 is COOH.
10. The compound of claim 1 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 3 is COOH;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.
11. The kit of claim 4 , wherein the compound of Formula (IIA) is:
or a pharmaceutically acceptable salt thereof.
12. The kit of claim 4 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.
13. The kit of claim 12 , wherein R 3 is COOH.
14. The kit of claim 4 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 3 is COOH;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of claim 6 , wherein the compound of Formula (IIA) is:
or a pharmaceutically acceptable salt thereof.
16. The pharmaceutical composition of claim 6 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.
17. The pharmaceutical composition of claim 16 , wherein R 3 is COOH.
18. The pharmaceutical composition of claim 6 , wherein:
R 1 is phenyl;
R 2 is N[(CH 2 ) 7 NH 2 ] 2 ;
R 3 is COOH;
R 4 is phenyl;
R 5 is phenyl;
R 6 is CH 2 OH;
X is (CH 2 ) 2 ;
Y is (CH 2 ) 2 ;
W is O; and
U is (CH 2 ) 2 ,
or a pharmaceutically acceptable salt thereof.