THIOAMIDE-CONTAINING COMPOSITIONS AND METHODS OF USE THEREOF
Provided herein are compositions and methods for preparing albumin-targeting moieties that feature a thioamide linkage. Methods to use the albumin targeting molecules to generate drugs with improved in vivo pharmacodynamics and biodistribution are described. Therapeutic compounds incorporating these thioamide linked albumin-targeting moieties are disclosed.
1 ) A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, C 1 -C 6 alkyl, or a protecting group;
R 2 is H, C 1 -C 6 alkyl, or a protecting group;
R 3 is H, C 1 -C 6 alkyl, or a protecting group;
X is a therapeutic drug; and
n is 0, 1, 2, 3, 4, or 5.
2 ) The compound of claim 1 , wherein n is 2 or 3.
3 ) The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, C 1 -C 6 alkyl, or a protecting group;
R 2 is H, C 1 -C 6 alkyl, or a protecting group;
R 3 is H, C 1 -C 6 alkyl, or a protecting group;
L 1 is a natural amino acid, an unnatural amino acid, or (X) q —(Y) r —(Z) s , wherein X is C 1 -C 30 alkyl, Y is C 10 -C 30 heteroaromatic, and Z is C 1 -C 12 alkyl, wherein any of the methylene groups in the alkyl group of L 1 may be replaced with —O—, NH, or carbonyl;
R 4 is H, C 1 -C 6 alkyl, or a protecting group;
R 5 is H, C 1 -C 6 alkyl, or a protecting group;
R 6 is a therapeutic drug or chelating agent;
R 7 is H, C 1 -C 6 alkyl, or a protecting group;
R 8 is H, C 1 -C 6 alkyl, or a protecting group;
L 2 is a bond, —N(R 9 )—C 1 -C 12 alkyl-C(O)—, —N(R 9 )—C 4 -C 30 alkylcycloalkyl-C(O)—C 7 -C 30 alkylaryl-C(O)—, or —N(R 9 )—C 7 -C 30 alkylaryl-C(O)NH—C 7 -C 30 alkylaryl-C(O)NH—CH(CO 2 H)—C 1 -C 12 alkyl-NHC(O)—C 1 -C 12 alkyl-C(O)—, wherein C 7 -C 30 alkylaryl is optionally substituted with halo or hydroxyl;
n is 0, 1, 2, 3, 4, or 5;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, 3, 4, or 5;
q is 0 or 1;
r is 0 or 1; and
s is 0 or 1.
4 ) The compound of claim 3 , wherein n is 3.
5 ) The compound of claim 3 , wherein L 1 is X—Y—Z, and wherein:
X is
Y is
Z is C 1 -C 12 alkyl, wherein any of the methylene groups in the alkyl group may be replaced with NH or carbonyl.
6 ) The compound of claim 3 , wherein L 1 is Z, and wherein:
Z is C 1 -C 12 alkyl, wherein any of the methylene groups in the alkyl group may be replaced with NH or carbonyl.
7 ) The compound of claim 6 , wherein Z is
8 ) The compound of claim 1 , wherein the chelating agent is
9 ) The compound of claim 1 , wherein L 2 is —N(R 9 )—C 1 -C 12 alkyl-C(O)—.
10 ) The compound of claim 9 , wherein L 2 is
11 ) The compound of claim 1 , wherein L 2 is —N(R 9 )—C 4 -C 30 alkylcycloalkyl-C(O)—C 7 -C 30 alkylaryl-C(O)—.
12 ) The compound of claim 12 , wherein L 2 is
13 ) The compound of claim 1 , wherein L 2 is —N(R 9 )—C 7 -C 30 alkylaryl-C(O)NH—C 7 -C 30 alkylaryl-C(O)NH—CH(CO 2 H)—C 1 -C 12 alkyl-NHC(O)—C 1 -C 12 alkyl-C(O)—, wherein C 7 -C 30 alkylaryl is optionally substituted with halo or hydroxyl.
14 ) The compound of claim 13 , wherein L 2 is
15 ) The compound of claim 13 , wherein L 2 is
16 ) The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (III):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, C 1 -C 6 alkyl, or a protecting group;
R 2 is H, C 1 -C 6 alkyl, or a protecting group;
R 3 is H, C 1 -C 6 alkyl, or a protecting group;
L 1 is a natural amino acid, an unnatural amino acid, or (X) q —(Y) r —(Z) s , wherein X is C 1 -C 20 alkyl, Y is C 10 -C 30 aryl, and Z is C 1 -C 12 alkyl, wherein any of the methylene groups in the alkyl group of L 1 may be replaced with —O—, NH, carbonyl, or thiocarbonyl;
R 4 is H, C 1 -C 6 alkyl, or a protecting group;
R 5 is H, C 1 -C 6 alkyl, or a protecting group;
R 6 is a therapeutic drug or chelating agent;
R 7 is H, C 1 -C 6 alkyl, or a protecting group;
R 8 is H, C 1 -C 6 alkyl, or a protecting group;
R 9 is H, C 1 -C 6 alkyl, or a protecting group;
R 10 is H, C 1 -C 6 alkyl, or a protecting group;
L 2 is C 1 -C 30 alkyl-C 3 -C 18 heteroaryl-C 6 -C 18 aryl, wherein any of the methylene groups in the alkyl group may be replaced with —O—;
n is 0, 1, 2, 3, 4, or 5;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, 3, 4, or 5;
q is 0 or 1;
r is 0 or 1; and
s is 0 or 1.
17 ) The compound of claim 16 , wherein n is 3.
18 ) The compound of claim 16 , wherein L 1 is X—Y—Z, and wherein:
X is
Y is C 10 -C 30 aryl; and
Z is C 1 -C 12 alkyl, wherein any of the methylene groups in the alkyl group may be replaced with NH or carbonyl.
19 ) The compound of claim 16 , wherein the chelating agent is
20 ) The compound of claim 16 , wherein L 2 is
21 ) A compound of Formula (IV):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, C 1 -C 6 alkyl, or a protecting group;
R 2 is H, C 1 -C 6 alkyl, or a protecting group; and
n is 0, 1, 2, 3, 4, or 5.
22 ) The compound of claim 1 , wherein n is 2 or 3.